21 results on '"Murphy, Maureen E."'
Search Results
2. Abstract IA20: A coding region variant in the TP53 tumor-suppressor gene may underlie cancer disparities in African Americans
- Author
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Murphy, Maureen E., primary
- Published
- 2018
- Full Text
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3. Abstract 993: Wnt-er is coming: WNT5A promotes a slow cycling phenotype via p53 in conditions of stress
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Webster, Marie R., primary, Fane, Mitchell, additional, Kaur, Amanpreet, additional, Alicea, Gretchen, additional, Ecker, Brett L., additional, Ndoye, Abibatou, additional, Kugel, Curtis, additional, Basu, Subhasree, additional, Valiga, Alexander, additional, Appleton, Jessica L., additional, Murphy, Maureen E., additional, and Weeraratna, Ashani, additional
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- 2018
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4. Abstract 3775: p53 is differentially regulated in proliferative and invasive melanoma cells
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Webster, Marie R., primary, Basu, Subhasree, additional, Kaur, Amanpreet, additional, Appleton, Jessica, additional, Murphy, Maureen E., additional, and Weeraratna, Ashani T., additional
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- 2015
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5. HSP70 Inhibition Limits FAK-Dependent Invasion and Enhances the Response to Melanoma Treatment with BRAF Inhibitors.
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Budina-Kolomets, Anna, Webster, Marie R., Leu, Julia I-Ju, Jennis, Matthew, Krepler, Clemens, Guerrini, Anastasia, Kossenkov, Andrew V., Wei Xu, Karakousis, Giorgos, Schuchter, Lynn, Amaravadi, Ravi K., Hong Wu, Xiangfan Yin, Qin Liu, Yiling Lu, Mills, Gordon B., Xiaowei Xu, George, Donna L., Weeraratna, Ashani T., and Murphy, Maureen E.
- Subjects
- *
HSP70 heat-shock proteins , *FOCAL adhesion kinase , *MELANOMA treatment , *BRAF genes , *MOLECULAR chaperones - Abstract
The stress-inducible chaperone protein HSP70 (HSPA1) is implicated in melanoma development, and HSP70 inhibitors exert tumor-specific cytotoxic activity in cancer. In this study, we documented that a significant proportion of melanoma tumors express high levels of HSP70, particularly at advanced stages, and that phospho-FAK (PTK2) and BRAF are HSP70 client proteins. Treatment of melanoma cells with HSP70 inhibitors decreased levels of phospho-FAK along with impaired migration, invasion, and metastasis in vitro and in vivo. Moreover, the HSP70 inhibitor PET-16 reduced levels of mutant BRAF, synergized with the BRAF inhibitor PLX4032 in vitro, and enhanced the durability of response to BRAF inhibition in vivo. Collectively, these findings provide strong support for HSP70 inhibition as a therapeutic strategy in melanoma, especially as an adjuvant approach for overcoming the resistance to BRAF inhibitors frequently observed in melanoma patients. Cancer Res; 76(9); 2720-30. [ABSTRACT FROM AUTHOR]
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- 2016
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6. The African-centric P47S Variant of TP53 Confers Immune Dysregulation and Impaired Response to Immune Checkpoint Inhibition.
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Stieg DC, Parris JLD, Yang THL, Mirji G, Reiser SK, Murali N, Werts M, Barnoud T, Lu DY, Shinde R, Murphy ME, and Claiborne DT
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- Humans, Mice, Animals, Immune Checkpoint Inhibitors, Genes, p53, Germ-Line Mutation, Tumor Microenvironment genetics, Tumor Suppressor Protein p53 genetics, Li-Fraumeni Syndrome genetics
- Abstract
The tumor suppressor TP53 is the most frequently mutated gene in cancer and is mutationally inactivated in 50% of sporadic tumors. Inactivating mutations in TP53 also occur in Li Fraumeni syndrome (LFS). In addition to germline mutations in TP53 in LFS that completely inactivate this protein, there are many more germline mutant forms of TP53 in human populations that partially inactivate this protein: we call these partially inactivating mutations "hypomorphs." One of these hypomorphs is a SNP that exists in 6%-10% of Africans and 1%-2% of African Americans, which changes proline at amino acid 47 to serine (Pro47Ser; P47S). We previously showed that the P47S variant of p53 is intrinsically impaired for tumor suppressor function, and that this SNP is associated with increased cancer risk in mice and humans. Here we show that this SNP also influences the tumor microenvironment, and the immune microenvironment profile in P47S mice is more protumorigenic. At basal levels, P47S mice show impaired memory T-cell formation and function, along with increased anti-inflammatory (so-called "M2") macrophages. We show that in tumor-bearing P47S mice, there is an increase in immunosuppressive myeloid-derived suppressor cells and decreased numbers of activated dendritic cells, macrophages, and B cells, along with evidence for increased T-cell exhaustion in the tumor microenvironment. Finally, we show that P47S mice demonstrate an incomplete response to anti-PD-L1 therapy. Our combined data suggest that the African-centric P47S variant leads to both intrinsic and extrinsic defects in tumor suppression., Significance: Findings presented here show that the P47S variant of TP53 influences the immune microenvironment, and the immune response to cancer. This is the first time that a naturally occurring genetic variant of TP53 has been shown to negatively impact the immune microenvironment and the response to immunotherapy., (© 2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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7. An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.
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Indeglia A, Leung JC, Miller SA, Leu JI, Dougherty JF, Clarke NL, Kirven NA, Shao C, Ke L, Lovell S, Barnoud T, Lu DY, Lin C, Kannan T, Battaile KP, Yang THL, Batista Oliva I, Claiborne DT, Vogel P, Liu L, Liu Q, Nefedova Y, Cassel J, Auslander N, Kossenkov AV, Karanicolas J, and Murphy ME
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- Animals, Humans, Mice, African People genetics, Genes, p53, Neoplasms genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors., Significance: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy. See related commentary by Bhatta and Cooks, p. 1518. This article is highlighted in the In This Issue feature, p. 1501., (2023 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2023
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8. p53 Oligomerization Domain Mutants: A New Class of Mutants That Retain "License to Kill".
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Stieg D, Casey K, and Murphy ME
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- Humans, Tumor Suppressor Protein p53 metabolism, Transcriptional Activation, Cell Death, Li-Fraumeni Syndrome metabolism
- Abstract
Summary: In this issue of Cancer Discovery, companion articles from the Prives and Lozano groups describe functional analyses of a common dimeric mutant of p53 found in Li-Fraumeni disease and sporadic cancer: A347D (AD). The authors show that the AD mutant is completely defective for canonical p53 transcriptional function, but interestingly retains some tumor suppressor function, which they show is manifested as "neomorphic" activities in transcription and the control of mitochondrial metabolism. See related article by Gencel-Augusto et al., p. 1230 (7). See related article by Choe et al., p. 1250 (6)., (©2023 American Association for Cancer Research.)
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- 2023
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9. HSP70 inhibition blocks adaptive resistance and synergizes with MEK inhibition for the treatment of NRAS-mutant melanoma.
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Parris JLD, Barnoud T, Leu JI, Leung JC, Ma W, Kirven NA, Poli ANR, Kossenkov AV, Liu Q, Salvino JM, George DL, Weeraratna AT, Chen Q, and Murphy ME
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- Mice, Animals, GTP Phosphohydrolases genetics, Membrane Proteins genetics, Mutation, Protein Kinase Inhibitors pharmacology, Tumor Microenvironment, Mitogen-Activated Protein Kinase Kinases, Melanoma drug therapy
- Abstract
NRAS-mutant melanoma is currently a challenge to treat. This is due to an absence of inhibitors directed against mutant NRAS, along with adaptive and acquired resistance of this tumor type to inhibitors in the MAPK pathway. Inhibitors to MEK (mitogen-activated protein kinase kinase) have shown some promise for NRAS-mutant melanoma. In this work we explored the use of MEK inhibitors for NRAS-mutant melanoma. At the same time we investigated the impact of the brain microenvironment, specifically astrocytes, on the response of a melanoma brain metastatic cell line to MEK inhibition. These parallel avenues led to the surprising finding that astrocytes enhance the sensitivity of melanoma tumors to MEK inhibitors (MEKi). We show that MEKi cause an upregulation of the transcription factor ID3, which confers resistance. This upregulation of ID3 is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEK inhibitors, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEK inhibitors against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma., Significance: MEK inhibitors are currently used for NRAS-mutant melanoma, but have shown modest efficacy as single agents. This research shows a synergistic effect of combining HSP70 inhibitors with MEK inhibitors for the treatment of NRAS mutant melanoma., Competing Interests: Conflict of interests: The authors report no conflict of interest
- Published
- 2021
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10. A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors.
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Barnoud T, Leung JC, Leu JI, Basu S, Poli ANR, Parris JLD, Indeglia A, Martynyuk T, Good M, Gnanapradeepan K, Sanseviero E, Moeller R, Tang HY, Cassel J, Kossenkov AV, Liu Q, Speicher DW, Gabrilovich DI, Salvino JM, George DL, and Murphy ME
- Subjects
- Adenosine Triphosphate metabolism, Alarmins metabolism, Animals, Cell-Free System, Colorectal Neoplasms immunology, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, HMGB1 Protein metabolism, HT29 Cells, High-Throughput Screening Assays, Humans, Male, Mice, Inbred C57BL, Mice, Inbred NOD, Mitochondria metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Colorectal Neoplasms drug therapy, HSP70 Heat-Shock Proteins antagonists & inhibitors, Mitochondria drug effects
- Abstract
The protein chaperone HSP70 is overexpressed in many cancers including colorectal cancer, where overexpression is associated with poor survival. We report here the creation of a uniquely acting HSP70 inhibitor (HSP70i) that targets multiple compartments in the cancer cell, including mitochondria. This inhibitor was mitochondria toxic and cytotoxic to colorectal cancer cells, but not to normal colon epithelial cells. Inhibition of HSP70 was efficacious as a single agent in primary and metastatic models of colorectal cancer and enabled identification of novel mitochondrial client proteins for HSP70. In a syngeneic colorectal cancer model, the inhibitor increased immune cell recruitment into tumors. Cells treated with the inhibitor secreted danger-associated molecular patterns (DAMP), including ATP and HMGB1, and functioned effectively as a tumor vaccine. Interestingly, the unique properties of this HSP70i in the disruption of mitochondrial function and the inhibition of proteostasis both contributed to DAMP release. This HSP70i constitutes a promising therapeutic opportunity in colorectal cancer and may exhibit antitumor activity against other tumor types. SIGNIFICANCE: These findings describe a novel HSP70i that disrupts mitochondrial proteostasis, demonstrating single-agent efficacy that induces immunogenic cell death in treated tumors., (©2020 American Association for Cancer Research.)
- Published
- 2020
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11. A Rare TP53 Mutation Predominant in Ashkenazi Jews Confers Risk of Multiple Cancers.
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Powers J, Pinto EM, Barnoud T, Leung JC, Martynyuk T, Kossenkov AV, Philips AH, Desai H, Hausler R, Kelly G, Le AN, Li MM, MacFarland SP, Pyle LC, Zelley K, Nathanson KL, Domchek SM, Slavin TP, Weitzel JN, Stopfer JE, Garber JE, Joseph V, Offit K, Dolinsky JS, Gutierrez S, McGoldrick K, Couch FJ, Levin B, Edelman MC, Levy CF, Spunt SL, Kriwacki RW, Zambetti GP, Ribeiro RC, Murphy ME, and Maxwell KN
- Subjects
- Adult, Age of Onset, Female, Germ-Line Mutation, Humans, Jews, Male, Mutation, Missense, Pedigree, Genetic Predisposition to Disease genetics, Li-Fraumeni Syndrome genetics, Neoplasms genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li-Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53 . The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3 , and LCN15 ) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. SIGNIFICANCE: TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish-predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk., (©2020 American Association for Cancer Research.)
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- 2020
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12. Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis.
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Zou Y, Watters A, Cheng N, Perry CE, Xu K, Alicea GM, Parris JLD, Baraban E, Ray P, Nayak A, Xu X, Herlyn M, Murphy ME, Weeraratna AT, Schug ZT, and Chen Q
- Subjects
- Animals, Astrocytes cytology, Astrocytes pathology, Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Line, Tumor, Cell Movement, Cell Proliferation, Gene Expression Profiling, Humans, Mice, Neoplasm Transplantation, Signal Transduction, Astrocytes metabolism, Brain Neoplasms pathology, Brain Neoplasms secondary, Fatty Acids, Unsaturated metabolism, PPAR gamma genetics
- Abstract
Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading cancer cells and the brain cells. Peroxisome proliferator-activated receptor γ (PPARγ) has ambiguous functions in cancer development, and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glial cells, activate PPARγ in brain metastatic cancer cells. PPARγ activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that act as "donors" of PPARγ activators to the invading cancer cells. In clinical samples, PPARγ signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPARγ antagonists significantly reduces brain metastatic burden in vivo . Our study clarifies a prometastatic role for PPARγ signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPARγ blockade to treat brain metastasis. SIGNIFICANCE: Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPARγ signaling. This protumor effect of PPARγ in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPARγ has diverse functions at different stages of cancer development. This article is highlighted in the In This Issue feature, p. 1631 ., (©2019 American Association for Cancer Research.)
- Published
- 2019
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13. The Codon 72 TP53 Polymorphism Contributes to TSC Tumorigenesis through the Notch-Nodal Axis.
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Cho JH, Patel B, Bonala S, Mansouri H, Manne S, Vadrevu SK, Ghouse S, Kung CP, Murphy ME, Astrinidis A, Henske EP, Kwiatkowski DJ, Markiewski MM, and Karbowniczek M
- Subjects
- Angiomyolipoma genetics, Angiomyolipoma metabolism, Angiomyolipoma pathology, Animals, Carcinogenesis genetics, Carcinogenesis metabolism, Cell Movement, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms genetics, Kidney Neoplasms metabolism, Kidney Neoplasms pathology, Mice, Mutation, Nodal Protein genetics, Receptor, Notch1 genetics, Tuberous Sclerosis genetics, Tuberous Sclerosis metabolism, Tuberous Sclerosis Complex 1 Protein genetics, Tuberous Sclerosis Complex 1 Protein metabolism, Tumor Cells, Cultured, Tumor Suppressor Protein p53 genetics, Carcinogenesis pathology, Nodal Protein metabolism, Polymorphism, Single Nucleotide, Receptor, Notch1 metabolism, Tuberous Sclerosis pathology, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 physiology
- Abstract
We discovered that 90.3% of patients with angiomyolipomas, lymphangioleiomyomatosis (LAM), and tuberous sclerosis complex (TSC) carry the arginine variant of codon 72 (R72) of TP53 and that R72 increases the risk for angiomyolipoma. R72 transactivates NOTCH1 and NODAL better than the proline variant of codon 72 (P72); therefore, the expression of NOTCH1 and NODAL is increased in angiomyolipoma cells that carry R72. The loss of Tp53 and Tsc1 within nestin-expressing cells in mice resulted in the development of renal cell carcinomas (RCC) with high Notch1 and Nodal expression, suggesting that similar downstream mechanisms contribute to tumorigenesis as a result of p53 loss in mice and p53 polymorphism in humans. The loss of murine Tp53 or expression of human R72 contributes to tumorigenesis via enhancing epithelial-to-mesenchymal transition and motility of tumor cells through the Notch and Nodal pathways. IMPLICATIONS: This work revealed unexpected contributions of the p53 polymorphism to the pathogenesis of TSC and established signaling alterations caused by this polymorphism as a target for therapy. We found that the codon 72 TP53 polymorphism contributes to TSC-associated tumorigenesis via Notch and Nodal signaling., (©2019 American Association for Cancer Research.)
- Published
- 2019
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14. Tailoring Chemotherapy for the African-Centric S47 Variant of TP53.
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Barnoud T, Budina-Kolomets A, Basu S, Leu JI, Good M, Kung CP, Liu J, Liu Q, Villanueva J, Zhang R, George DL, and Murphy ME
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- Africa, Black or African American genetics, Alleles, Animals, Apoptosis, Black People genetics, Cell Death drug effects, Cell Line, Tumor, Cell Transformation, Neoplastic, Cisplatin pharmacology, Disease Progression, Fibroblasts metabolism, Genotype, Humans, Mice, Mitochondria metabolism, Mutation drug effects, Neoplasm Transplantation, Pharmacogenetics, Precision Medicine, Risk, Polymorphism, Single Nucleotide, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
The tumor suppressor TP53 is the most frequently mutated gene in human cancer and serves to restrict tumor initiation and progression. Single-nucleotide polymorphisms (SNP) in TP53 and p53 pathway genes can have a marked impact on p53 tumor suppressor function, and some have been associated with increased cancer risk and impaired response to therapy. Approximately 6% of Africans and 1% of African Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser). This SNP impairs p53-mediated apoptosis in response to radiation and genotoxic agents and is associated with increased cancer risk in humans and in a mouse model. In this study, we compared the ability of wild-type (WT) and S47 p53 to suppress tumor development and respond to therapy. Our goal was to find therapeutic compounds that are more, not less, efficacious in S47 tumors. We identified the superior efficacy of two agents, cisplatin and BET inhibitors, on S47 tumors compared with WT. Cisplatin caused dramatic decreases in the progression of S47 tumors by activating the p53/PIN1 axis to drive the mitochondrial cell death program. These findings serve as important proof of principle that chemotherapy can be tailored to p53 genotype. Significance: A rare African-derived radioresistant p53 SNP provides proof of principle that chemotherapy can be tailored to TP53 genotype. Cancer Res; 78(19); 5694-705. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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15. ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma.
- Author
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Ndoye A, Budina-Kolomets A, Kugel CH 3rd, Webster MR, Kaur A, Behera R, Rebecca VW, Li L, Brafford PA, Liu Q, Gopal YNV, Davies MA, Mills GB, Xu X, Wu H, Herlyn M, Nicastri MC, Winkler JD, Soengas MS, Amaravadi RK, Murphy ME, and Weeraratna AT
- Subjects
- Aminoquinolines pharmacology, Animals, Autophagy drug effects, Autophagy-Related Protein 5 metabolism, Blotting, Western, Cell Line, Tumor, Feedback, Physiological drug effects, Gene Expression Regulation, Neoplastic, Humans, Melanoma metabolism, Melanoma pathology, Mice, Polyamines pharmacology, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Wnt Signaling Pathway drug effects, Wnt-5a Protein genetics, Wnt-5a Protein metabolism, beta Catenin genetics, beta Catenin metabolism, Autophagy genetics, Autophagy-Related Protein 5 genetics, Melanoma genetics, Wnt Signaling Pathway genetics
- Abstract
Autophagy mediates resistance to various anticancer agents. In melanoma, resistance to targeted therapy has been linked to expression of Wnt5A, an intrinsic inhibitor of β-catenin, which also promotes invasion. In this study, we assessed the interplay between Wnt5A and autophagy by combining expression studies in human clinical biopsies with functional analyses in cell lines and mouse models. Melanoma cells with high Wnt5A and low β-catenin displayed increased basal autophagy. Genetic blockade of autophagy revealed an unexpected feedback loop whereby knocking down the autophagy factor ATG5 in Wnt5A
high cells decreased Wnt5A and increased β-catenin. To define the physiologic relevance of this loop, melanoma cells with different Wnt status were treated in vitro and in vivo with the potent lysosomotropic compound Lys05. Wnt5Ahigh cells were less sensitive to Lys05 and could be reverted by inducing β-catenin activity. Our results suggest the efficacy of autophagy inhibitors might be improved by taking the Wnt signature of melanoma cells into account. Cancer Res; 77(21); 5873-85. ©2017 AACR ., (©2017 American Association for Cancer Research.)- Published
- 2017
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16. A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles.
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Rebecca VW, Nicastri MC, McLaughlin N, Fennelly C, McAfee Q, Ronghe A, Nofal M, Lim CY, Witze E, Chude CI, Zhang G, Alicea GM, Piao S, Murugan S, Ojha R, Levi SM, Wei Z, Barber-Rotenberg JS, Murphy ME, Mills GB, Lu Y, Rabinowitz J, Marmorstein R, Liu Q, Liu S, Xu X, Herlyn M, Zoncu R, Brady DC, Speicher DW, Winkler JD, and Amaravadi RK
- Subjects
- Animals, Antimalarials administration & dosage, Antineoplastic Agents administration & dosage, Autophagy drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Chloroquine administration & dosage, Humans, Lysosomes genetics, Mechanistic Target of Rapamycin Complex 1 antagonists & inhibitors, Mechanistic Target of Rapamycin Complex 1 genetics, Melanoma genetics, Melanoma pathology, Membrane Proteins genetics, Mice, Molecular Targeted Therapy, Proteolysis drug effects, Signal Transduction drug effects, Thiolester Hydrolases genetics, Lysosomes drug effects, Melanoma drug therapy, Membrane Proteins antagonists & inhibitors, TOR Serine-Threonine Kinases genetics, Thiolester Hydrolases antagonists & inhibitors
- Abstract
Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e., autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic cancer, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer. Significance: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. Cancer Discov; 7(11); 1266-83. ©2017 AACR. See related commentary by Towers and Thorburn, p. 1218 This article is highlighted in the In This Issue feature, p. 1201 ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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17. Identification of TRIML2, a novel p53 target, that enhances p53 SUMOylation and regulates the transactivation of proapoptotic genes.
- Author
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Kung CP, Khaku S, Jennis M, Zhou Y, and Murphy ME
- Subjects
- Animals, Apoptosis, Cells, Cultured, Fibroblasts cytology, Fibroblasts metabolism, Gene Knock-In Techniques, HCT116 Cells, Humans, Mice, Molecular Sequence Data, Mutation, Oligonucleotide Array Sequence Analysis, Sumoylation, Tumor Suppressor Protein p53 metabolism, Carrier Proteins genetics, Carrier Proteins metabolism, Tumor Suppressor Protein p53 genetics
- Abstract
Unlabelled: The tumor-suppressor protein p53, encoded by TP53, inhibits tumorigenesis by inducing cell-cycle arrest, senescence, and apoptosis. Several genetic polymorphisms exist in TP53, including a proline to arginine variant at amino acid 72 (P72 and R72, respectively); this polymorphism alters p53 function. In general, the P72 variant shows increased ability to induce cell-cycle arrest, whereas the R72 variant possesses increased ability to induce apoptosis, relative to P72. At present, the underlying mechanisms for these functional differences are not fully understood. Toward elucidating the molecular basis for these differences, a gene-expression microarray analysis was conducted on normal human fibroblast cells that are homozygous for P72 and R72 variants, along with subclones of these lines that express a p53 short hairpin (shp53). Approximately three dozen genes were identified whose transactivation is affected by the codon 72 polymorphism. One of these is the tripartite-motif family-like 2 (TRIML2) gene, which is preferentially induced by the R72 variant. Importantly, the accumulated data indicate that TRIML2 interacts with p53, and facilitates the modification of p53 with SUMO2. TRIML2 also enhances the ability of p53 to transactivate a subset of proapoptotic target genes associated with prolonged oxidative stress, including PIDD, PIG3 (TP53I3), and PIG6 (PRODH). These data indicate that TRIML2 is part of a feed-forward loop that activates p53 in cells expressing the R72 variant, particularly after prolonged stress., Implications: The defined actions of TRIML2, in part, explain the underlying molecular basis for increased apoptotic potential of the R72 variant of p53., (©2014 American Association for Cancer Research.)
- Published
- 2015
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18. A modified HSP70 inhibitor shows broad activity as an anticancer agent.
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Balaburski GM, Leu JI, Beeharry N, Hayik S, Andrake MD, Zhang G, Herlyn M, Villanueva J, Dunbrack RL Jr, Yen T, George DL, and Murphy ME
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- Animals, Computer Simulation, Gene Expression Regulation, Leukemic, Genomic Instability drug effects, HSP72 Heat-Shock Proteins genetics, HSP72 Heat-Shock Proteins metabolism, Humans, Mice, Models, Molecular, Molecular Docking Simulation, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Protein Binding drug effects, Protein Structure, Tertiary drug effects, Structure-Activity Relationship, Substrate Specificity, Antineoplastic Agents administration & dosage, HSP72 Heat-Shock Proteins antagonists & inhibitors, Neoplasms, Experimental drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Sulfonamides administration & dosage
- Abstract
The stress-induced HSP70 is an ATP-dependent molecular chaperone that plays a key role in refolding misfolded proteins and promoting cell survival following stress. HSP70 is marginally expressed in nontransformed cells, but is greatly overexpressed in tumor cells. Silencing HSP70 is uniformly cytotoxic to tumor but not normal cells; therefore, there has been great interest in the development of HSP70 inhibitors for cancer therapy. Here, we report that the HSP70 inhibitor 2-phenylethynesulfonamide (PES) binds to the substrate-binding domain of HSP70 and requires the C-terminal helical "lid" of this protein (amino acids 573-616) to bind. Using molecular modeling and in silico docking, we have identified a candidate binding site for PES in this region of HSP70, and we identify point mutants that fail to interact with PES. A preliminary structure-activity relationship analysis has revealed a derivative of PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), which shows increased cytotoxicity and ability to inhibit autophagy, along with significantly improved ability to extend the life of mice with pre-B-cell lymphoma, compared with the parent compound (P = 0.015). Interestingly, we also show that these HSP70 inhibitors impair the activity of the anaphase promoting complex/cyclosome (APC/C) in cell-free extracts, and induce G2-M arrest and genomic instability in cancer cells. PES-Cl is thus a promising new anticancer compound with several notable mechanisms of action.
- Published
- 2013
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19. HSP70 inhibition by the small-molecule 2-phenylethynesulfonamide impairs protein clearance pathways in tumor cells.
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Leu JI, Pimkina J, Pandey P, Murphy ME, and George DL
- Subjects
- Animals, Benzoquinones pharmacology, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, HSP70 Heat-Shock Proteins metabolism, Humans, Lactams, Macrocyclic pharmacology, Lysosomes metabolism, Mice, Mice, Nude, Neoplasm Proteins metabolism, Neoplasms metabolism, Proteasome Endopeptidase Complex metabolism, Sulfonamides therapeutic use, Xenograft Model Antitumor Assays, Autophagy drug effects, HSP70 Heat-Shock Proteins antagonists & inhibitors, Neoplasms drug therapy, Sulfonamides pharmacology
- Abstract
The evolutionarily conserved stress-inducible HSP70 molecular chaperone plays a central role in maintaining protein quality control in response to various forms of stress. Constitutively elevated HSP70 expression is a characteristic of many tumor cells and contributes to their survival. We recently identified the small-molecule 2-phenylethyenesulfonamide (PES) as a novel HSP70 inhibitor. Here, we present evidence that PES-mediated inhibition of HSP70 family proteins in tumor cells results in an impairment of the two major protein degradation systems, namely, the autophagy-lysosome system and the proteasome pathway. HSP70 family proteins work closely with the HSP90 molecular chaperone to maintain the stability and activities of their many client proteins, and PES causes a disruption in the HSP70/HSP90 chaperone system. As a consequence, many cellular proteins, including known HSP70/HSP90 substrates, accumulate in detergent-insoluble cell fractions, indicative of aggregation and functional inactivation. Overall, PES simultaneously disrupts several cancer critical survival pathways, supporting the idea of targeting HSP70 as a potential approach for cancer therapeutics., (©2011 AACR.)
- Published
- 2011
- Full Text
- View/download PDF
20. The ARF tumor suppressor can promote the progression of some tumors.
- Author
-
Humbey O, Pimkina J, Zilfou JT, Jarnik M, Dominguez-Brauer C, Burgess DJ, Eischen CM, and Murphy ME
- Subjects
- Animals, Autophagy genetics, Cyclin-Dependent Kinase Inhibitor p16 biosynthesis, Disease Progression, Fibroblasts, Gene Silencing, Humans, Lymphoma, B-Cell metabolism, Lymphoma, B-Cell pathology, Mice, Mice, Knockout, Mice, SCID, RNA, Messenger biosynthesis, RNA, Messenger genetics, Tumor Suppressor Protein p53 biosynthesis, Tumor Suppressor Protein p53 genetics, Up-Regulation, Cyclin-Dependent Kinase Inhibitor p16 genetics, Genes, Tumor Suppressor, Lymphoma, B-Cell genetics
- Abstract
p14/p19ARF (ARF) is a tumor suppressor gene that is frequently mutated in human cancer. ARF has multiple tumor suppressor functions, some of which are mediated by signaling to p53. Surprisingly, a significant fraction of human tumors retain persistently high levels of ARF, suggesting that ARF may possess a prosurvival function. We show that ARF protein is markedly up-regulated in cells exposed to nutrient starvation. Cells with silenced ARF show reduced autophagy and reduced viability when placed under conditions of starvation. We show for the first time that ARF silencing can limit the progression of some tumors, such as lymphoma, but not others, such as E1A/Ras-induced tumors. Specifically, myc-driven lymphomas with mutant p53 tend to overexpress ARF; we show that silencing ARF in these tumors greatly impedes their progression. These data are the first to show that ARF can act in a p53-independent manner to promote the progression of some tumors.
- Published
- 2008
- Full Text
- View/download PDF
21. Regulation of cell death in oncogenesis.
- Author
-
Murphy ME
- Subjects
- Animals, Humans, Apoptosis physiology, Cell Transformation, Neoplastic pathology, Neoplasms pathology
- Published
- 2005
- Full Text
- View/download PDF
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