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8. Lysine deacetylase inhibitors have low selectivity in cells and exhibit predominantly off‐target effects.

Author

Bornes, Kiara E., Moody, Marcus A., Huckaba, Thomas M., Benz, Megan C., McConnell, Emily C., Foroozesh, Maryam, Barnes, Van H., Collins‐Burow, Bridgette M., Burow, Matthew E., Watt, Terry J., and Toro, Tasha B.

Subjects
HISTONE acetylation, GENE expression, DEACETYLASES, LYSINE, DEACETYLATION
Abstract

Lysine deacetylases (KDACs or HDACs) are metal‐dependent enzymes that regulate lysine acetylation, a post‐translational modification that is present on thousands of human proteins, essential for many cellular processes, and often misregulated in diseases. The selective inhibition of KDACs would allow for understanding of the biological roles of individual KDACs and therapeutic targeting of individual enzymes. Recent studies have suggested that purportedly specific KDAC inhibitors have significant off‐target binding, but the biological consequences of off‐target binding were not evaluated. We compared the effects of treatment with two of the reportedly most KDAC‐selective inhibitors, Tubastatin A and PCI‐34051, in HT1080 cells in which the endogenous KDAC6 or KDAC8 gene has been mutated to inactivate enzyme catalysis while retaining enzyme expression. Genetic inactivation results in much stronger deacetylation defects on known targets compared to inhibitor treatment. Gene expression analysis revealed that both inhibitors have extensive and extensively overlapping off‐target effects in cells, even at low inhibitor doses. Furthermore, Tubastatin A treatment led to increased histone acetylation, while inactivation of KDAC6 or KDAC8 did not. Genetic inactivation of KDAC6, but not KDAC8, impaired tumor formation in a xenograft model system, in contrast to previous reports with KDAC inhibitors suggesting the reverse. We conclude that the majority of observed biological effects of treatment with KDAC inhibitors are due to off‐target effects rather than the intended KDAC inhibition. Developing a truly specific KDAC6 inhibitor could be a promising therapeutic avenue, but it is imperative to develop new inhibitors that selectively mimic genetic inactivation of individual KDACs. [ABSTRACT FROM AUTHOR]

Published
2025
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14. Unraveling the Impact of Aspergillus sojae —A Food-Grade Fungus—On Phytoalexins, Phenolic Acids, and the Antioxidant and Antidiabetic Activity of Different Legumes.

Author

Rana, Shalika, Broussard, William, Elliott, Steven, Burow, Matthew E., and Boue, Stephen M.

Subjects
LEGUME seeds, CHLOROGENIC acid, CAFFEIC acid, FERULIC acid, CHICKPEA, KIDNEY bean
Abstract

Legumes are a rich source of polyphenolic compounds known for their ability to promote health. Under stress conditions, legumes have been shown to produce higher levels of secondary metabolites, as a defensive mechanism. Hence, the present study aimed to induce legume seeds (e.g., soybean, chickpea, green pea, and red kidney bean) by inoculating them with Aspergillus sojae (A. sojae) and to evaluate the extracts for phytoalexins, phenolics, and antioxidant, antiobesity, and antidiabetic potentials. The UPLC-DAD findings of A. sojae-induced legumes showed medicarpin and maackiain in chickpea, pisatin in green pea, glyceollin I-III in soybean, and kievitone and phaseollin in red kidney bean. All induced legumes exhibited a higher total polyphenol content compared to the non-induced ones. Among induced legumes, soybean exhibited a higher (4.85 mg GAE/g) polyphenol content. The UPLC-ESI-QTOF-MS/MS findings established that legumes contained substantial levels of protocatechuic acid, vanillic acid, ferulic acid, chlorogenic acid, coumaric acid, 4-hydroxybenzoic acid, and caffeic acid. The results of antioxidant assays revealed a significantly higher level of activity in induced red kidney bean and soybean, whereas the level of activity in non-induced legumes was markedly lower. Moreover, induced red kidney bean effectively inhibited α-glucosidase (87.2%) and α-amylase (63.90%) at 5 mg/mL. Additionally, the maximum lipase inhibitory effects were displayed by induced soybean (72.54%) at 20 mg/mL. [ABSTRACT FROM AUTHOR]

Published
2024
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15. Obesity and leptin in breast cancer angiogenesis.

Author

Lagarde, Courtney B., Thapa, Kapil, Cullen, Nicole M., Hawes, Mackenzie L., Salim, Khudeja, Benz, Megan C., Dietrich, Sophie R., Burow, Brandon E., Bunnell, Bruce A., Martin, Elizabeth C., Collins-Burow, Bridgette M., Lynch, Ronald M., Hoang, Van T., Burow, Matthew E., and Fang, Jennifer S.

Subjects
METASTATIC breast cancer, CANCER prognosis, BREAST cancer, CANCER diagnosis, TUMOR microenvironment, BODY mass index
Abstract

At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm³ in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients. [ABSTRACT FROM AUTHOR]

Published
2024
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18. Context-Dependent Estrogenic Actions of (+)-Pisatin Produced in Elicited Green or Snow Pea (Pisum sativum)

Author

Belgodere, Jorge A., Benz, Megan C., Kpeli, G. Wills, Elliott, Jack R., Elliott, Steven, North, Jack D., Ponder, Isaac J., Ma, Peng, Dietrich, Sophie R., Cheng, Thomas, Nguyen, Khoa, Tilghman, Syreeta L., McLachlan, John A., Zou, Binghao, Anbalagan, Muralidharan, Rowan, Brian, Mondrinos, Mark, Wiese, Thomas E., Hoang, Van T., Collins-Burow, Bridgette M., Martin, Elizabeth C., Burow, Matthew E., and Boué, Stephen M.

Abstract

Legumes are a predominant source of isoflavones, termed phytoestrogens, that mimic 17β-estradiol (E2). Phytoalexins are inducible isoflavones produced in plants subjected to environmental stressors (e.g., UV, heat, or fungi). This study investigated estrogenic activity of snow and green peas elicited with Aspergillus sojae. Elicited extracts increased estrogenic activity and proliferation of breast cancer cells (MCF-7 or T47D) in a dose-dependent manner but exhibited antiestrogenic activity when combined with synthetic E2. HPLC analysis of elicited pea extracts identified (+)-pisatin as the primary phytoalexin, which was produced significantly (p< 0.0001) more in snow pea compared to green pea. RNA sequencing results suggested potential functional effects on endothelial cells and tissue vascularization. Indeed, (+)-pisatin enhanced metrics of network assembly and maturation in a microphysiological model of bulk tissue vasculogenesis. Thus, context-dependent functional effects of (+)-pisatin and pharmacologically similar phytoestrogens on the entire tissue microenvironment should be considered in preclinical investigation as potential therapeutic agents.

Published
2024
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19. Obesity-associated epigenetic alterations and the obesity-breast cancer axis

Author

Lagarde, Courtney B., primary, Kavalakatt, Joachim, additional, Benz, Megan C., additional, Hawes, Mackenzie L., additional, Arbogast, Carter A., additional, Cullen, Nicole M., additional, McConnell, Emily C., additional, Rinderle, Caroline, additional, Hebert, Katherine L., additional, Khosla, Maninder, additional, Belgodere, Jorge A., additional, Hoang, Van T., additional, Collins-Burow, Bridgette M., additional, Bunnell, Bruce A., additional, Burow, Matthew E., additional, and Alahari, Suresh K., additional

Published
2024
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29. A novel screening approach comparing kinase activity of small molecule inhibitors with similar molecular structures and distinct biologic effects in triple-negative breast cancer to identify targetable signaling pathways

Author

Matossian, Margarite D., Burks, Hope E., Elliott, Steven, Hoang, Van T., Zuercher, William J., Wells, Carrow, Drewry, David H., Kapadia, Nirav, Chang, Tiffany, Yan, Thomas, Windsor, Gabrielle O., Nguyen, Khoa, Fang, Fang, Nephew, Kenneth P., Buechlein, Aaron, Rusch, Douglas B., Sabol, Rachel A., Ucar, Deniz A., Zabaleta, Jovanny, Miele, Lucio, Bunnell, Bruce A., Collins-Burow, Bridgette M., and Burow, Matthew E.

Published
2020
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30. A novel patient-derived xenograft model for claudin-low triple-negative breast cancer

Author

Matossian, Margarite D., Burks, Hope E., Bowles, Annie C., Elliott, Steven, Hoang, Van T., Sabol, Rachel A., Pashos, Nicholas C., O’Donnell, Benjamen, Miller, Kristin S., Wahba, Bahia M., Bunnell, Bruce A., Moroz, Krzysztof, Zea, Arnold H., Jones, Steven D., Ochoa, Augusto C., Al-Khami, Amir A., Hossain, Fokhrul, Riker, Adam I., Rhodes, Lyndsay V., Martin, Elizabeth C., Miele, Lucio, Burow, Matthew E., and Collins-Burow, Bridgette M.

Published
2018
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31. Supplementary Video 2 from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Author

Mukherjee, Debarati, primary, Previs, Rebecca A., primary, Haines, Corinne, primary, Al Abo, Muthana, primary, Juras, Patrick K., primary, Strickland, Kyle C., primary, Chakraborty, Binita, primary, Artham, Sandeep, primary, Whitaker, Regina S., primary, Hebert, Katherine, primary, Fontenot, Jake, primary, Patierno, Steven R., primary, Freedman, Jennifer A., primary, Lau, Frank H., primary, Burow, Matthew E., primary, Chang, Ching-Yi, primary, and McDonnell, Donald P., primary

Published
2023
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32. Supplementary Video 4 from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Author

Mukherjee, Debarati, primary, Previs, Rebecca A., primary, Haines, Corinne, primary, Al Abo, Muthana, primary, Juras, Patrick K., primary, Strickland, Kyle C., primary, Chakraborty, Binita, primary, Artham, Sandeep, primary, Whitaker, Regina S., primary, Hebert, Katherine, primary, Fontenot, Jake, primary, Patierno, Steven R., primary, Freedman, Jennifer A., primary, Lau, Frank H., primary, Burow, Matthew E., primary, Chang, Ching-Yi, primary, and McDonnell, Donald P., primary

Published
2023
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33. Supplementary Video 3 from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Author

Mukherjee, Debarati, primary, Previs, Rebecca A., primary, Haines, Corinne, primary, Al Abo, Muthana, primary, Juras, Patrick K., primary, Strickland, Kyle C., primary, Chakraborty, Binita, primary, Artham, Sandeep, primary, Whitaker, Regina S., primary, Hebert, Katherine, primary, Fontenot, Jake, primary, Patierno, Steven R., primary, Freedman, Jennifer A., primary, Lau, Frank H., primary, Burow, Matthew E., primary, Chang, Ching-Yi, primary, and McDonnell, Donald P., primary

Published
2023
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34. Supplementary Video 1 from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Author

Mukherjee, Debarati, primary, Previs, Rebecca A., primary, Haines, Corinne, primary, Al Abo, Muthana, primary, Juras, Patrick K., primary, Strickland, Kyle C., primary, Chakraborty, Binita, primary, Artham, Sandeep, primary, Whitaker, Regina S., primary, Hebert, Katherine, primary, Fontenot, Jake, primary, Patierno, Steven R., primary, Freedman, Jennifer A., primary, Lau, Frank H., primary, Burow, Matthew E., primary, Chang, Ching-Yi, primary, and McDonnell, Donald P., primary

Published
2023
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35. Data from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Author

Mukherjee, Debarati, primary, Previs, Rebecca A., primary, Haines, Corinne, primary, Al Abo, Muthana, primary, Juras, Patrick K., primary, Strickland, Kyle C., primary, Chakraborty, Binita, primary, Artham, Sandeep, primary, Whitaker, Regina S., primary, Hebert, Katherine, primary, Fontenot, Jake, primary, Patierno, Steven R., primary, Freedman, Jennifer A., primary, Lau, Frank H., primary, Burow, Matthew E., primary, Chang, Ching-Yi, primary, and McDonnell, Donald P., primary

Published
2023
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36. Supplementary Figures 1-4 and Tables 1-2 from Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Author

Mukherjee, Debarati, primary, Previs, Rebecca A., primary, Haines, Corinne, primary, Al Abo, Muthana, primary, Juras, Patrick K., primary, Strickland, Kyle C., primary, Chakraborty, Binita, primary, Artham, Sandeep, primary, Whitaker, Regina S., primary, Hebert, Katherine, primary, Fontenot, Jake, primary, Patierno, Steven R., primary, Freedman, Jennifer A., primary, Lau, Frank H., primary, Burow, Matthew E., primary, Chang, Ching-Yi, primary, and McDonnell, Donald P., primary

Published
2023
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38. Engineering dense tumor constructs via cellular contraction of extracellular matrix hydrogels.

Author

McKee, Jae A., Olsen, Elisabet A., Wills Kpeli, Gideon, Brooks, Moriah R., Beitollahpoor, Mohamadreza, Pesika, Noshir S., Burow, Matthew E., and Mondrinos, Mark J.

Abstract

Physical characteristics of solid tumors such as dense internal microarchitectures and pathological stiffness influence cancer progression and treatment. While it is routine to engineer culture substrates and scaffolds with elastic moduli that approximate tumors, these models often fail to capture characteristic internal microarchitectures such as densely compacted concentric ECM fibers at the stromal interface. Contractile mesenchymal cells can solve this engineering challenge by deforming, contracting, and compacting extracellular matrix (ECM) hydrogels to decrease tissue volume and increase tissue density. Here we demonstrate that allowing human fibroblasts of varying origins to freely contract collagen type I‐containing hydrogels co‐seeded with carcinoma cell spheroids produces a tissue engineered construct with structural features that mimic dense solid tumors in vivo. Morphometry and mechanical testing were conducted in tandem with biochemical analysis of proliferation and viability to confirm that dense carcinoma constructs engineered using this approach capture relevant physical characteristics of solid carcinomas in a tractable format that preserves viability and is amenable to extended culture. The reported method is adaptable to the use of multiple mesenchymal cell types and the inclusion of fibrin in the ECM combined with seeding of endothelial cells to produce prevascularized constructs. The physical dense carcinoma constructs engineered using this approach may provide more clinically relevant venues for studying cancer pathophysiology and the challenges associated with the delivery of macromolecular drugs and cellular immunotherapies to solid tumors. [ABSTRACT FROM AUTHOR]

Published
2024
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41. Targeting CaMKK2 Inhibits Actin Cytoskeletal Assembly to Suppress Cancer Metastasis

Author

Mukherjee, Debarati, primary, Previs, Rebecca A., additional, Haines, Corinne, additional, Al Abo, Muthana, additional, Juras, Patrick K., additional, Strickland, Kyle C., additional, Chakraborty, Binita, additional, Artham, Sandeep, additional, Whitaker, Regina S., additional, Hebert, Katherine, additional, Fontenot, Jake, additional, Patierno, Steven R., additional, Freedman, Jennifer A., additional, Lau, Frank H., additional, Burow, Matthew E., additional, Chang, Ching-Yi, additional, and McDonnell, Donald P., additional

Published
2023
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42. Figure S1 -S11 from Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

Author

Anbalagan, Muralidharan, primary, Sheng, Mei, primary, Fleischer, Brian, primary, Zhang, Yifang, primary, Gao, Yuanjun, primary, Hoang, Van, primary, Matossian, Margarite, primary, Burks, Hope E., primary, Burow, Matthew E., primary, Collins-Burow, Bridgette M., primary, Hangauer, David, primary, and Rowan, Brian G., primary

Published
2023
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43. Data from Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

Author

Anbalagan, Muralidharan, primary, Sheng, Mei, primary, Fleischer, Brian, primary, Zhang, Yifang, primary, Gao, Yuanjun, primary, Hoang, Van, primary, Matossian, Margarite, primary, Burks, Hope E., primary, Burow, Matthew E., primary, Collins-Burow, Bridgette M., primary, Hangauer, David, primary, and Rowan, Brian G., primary

Published
2023
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44. Suppl. Figure Legends from Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERα-negative Breast Cancers to Tamoxifen through ERα Reexpression

Author

Anbalagan, Muralidharan, primary, Sheng, Mei, primary, Fleischer, Brian, primary, Zhang, Yifang, primary, Gao, Yuanjun, primary, Hoang, Van, primary, Matossian, Margarite, primary, Burks, Hope E., primary, Burow, Matthew E., primary, Collins-Burow, Bridgette M., primary, Hangauer, David, primary, and Rowan, Brian G., primary

Published
2023
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46. Data from Sorafenib Enhances Pemetrexed Cytotoxicity through an Autophagy-Dependent Mechanism in Cancer Cells

Author

Bareford, M. Danielle, primary, Park, Margaret A., primary, Yacoub, Adly, primary, Hamed, Hossein A., primary, Tang, Yong, primary, Cruickshanks, Nichola, primary, Eulitt, Patrick, primary, Hubbard, Nisan, primary, Tye, Gary, primary, Burow, Matthew E., primary, Fisher, Paul B., primary, Moran, Richard G., primary, Nephew, Kenneth P., primary, Grant, Steven, primary, and Dent, Paul, primary

Published
2023
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47. Supplementary Figure 2 from Cytokine Receptor CXCR4 Mediates Estrogen-Independent Tumorigenesis, Metastasis, and Resistance to Endocrine Therapy in Human Breast Cancer

Author

Rhodes, Lyndsay V., primary, Short, Sarah P., primary, Neel, Nicole F., primary, Salvo, Virgilio A., primary, Zhu, Yun, primary, Elliott, Steven, primary, Wei, Yongkun, primary, Yu, Dihua, primary, Sun, Menghong, primary, Muir, Shannon E., primary, Fonseca, Juan P., primary, Bratton, Melyssa R., primary, Segar, Chris, primary, Tilghman, Syreeta L., primary, Sobolik-Delmaire, Tammy, primary, Horton, Linda W., primary, Zaja-Milatovic, Snjezana, primary, Collins-Burow, Bridgette M., primary, Wadsworth, Scott, primary, Beckman, Barbara S., primary, Wood, Charles E., primary, Fuqua, Suzanne A., primary, Nephew, Kenneth P., primary, Dent, Paul, primary, Worthylake, Rebecca A., primary, Curiel, Tyler J., primary, Hung, Mien-Chie, primary, Richmond, Ann, primary, and Burow, Matthew E., primary

Published
2023
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48. Supplementary Figure 3 from Cytokine Receptor CXCR4 Mediates Estrogen-Independent Tumorigenesis, Metastasis, and Resistance to Endocrine Therapy in Human Breast Cancer

Author

Rhodes, Lyndsay V., primary, Short, Sarah P., primary, Neel, Nicole F., primary, Salvo, Virgilio A., primary, Zhu, Yun, primary, Elliott, Steven, primary, Wei, Yongkun, primary, Yu, Dihua, primary, Sun, Menghong, primary, Muir, Shannon E., primary, Fonseca, Juan P., primary, Bratton, Melyssa R., primary, Segar, Chris, primary, Tilghman, Syreeta L., primary, Sobolik-Delmaire, Tammy, primary, Horton, Linda W., primary, Zaja-Milatovic, Snjezana, primary, Collins-Burow, Bridgette M., primary, Wadsworth, Scott, primary, Beckman, Barbara S., primary, Wood, Charles E., primary, Fuqua, Suzanne A., primary, Nephew, Kenneth P., primary, Dent, Paul, primary, Worthylake, Rebecca A., primary, Curiel, Tyler J., primary, Hung, Mien-Chie, primary, Richmond, Ann, primary, and Burow, Matthew E., primary

Published
2023
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49. Supplementary Figure 1 from Cytokine Receptor CXCR4 Mediates Estrogen-Independent Tumorigenesis, Metastasis, and Resistance to Endocrine Therapy in Human Breast Cancer

Author

Rhodes, Lyndsay V., primary, Short, Sarah P., primary, Neel, Nicole F., primary, Salvo, Virgilio A., primary, Zhu, Yun, primary, Elliott, Steven, primary, Wei, Yongkun, primary, Yu, Dihua, primary, Sun, Menghong, primary, Muir, Shannon E., primary, Fonseca, Juan P., primary, Bratton, Melyssa R., primary, Segar, Chris, primary, Tilghman, Syreeta L., primary, Sobolik-Delmaire, Tammy, primary, Horton, Linda W., primary, Zaja-Milatovic, Snjezana, primary, Collins-Burow, Bridgette M., primary, Wadsworth, Scott, primary, Beckman, Barbara S., primary, Wood, Charles E., primary, Fuqua, Suzanne A., primary, Nephew, Kenneth P., primary, Dent, Paul, primary, Worthylake, Rebecca A., primary, Curiel, Tyler J., primary, Hung, Mien-Chie, primary, Richmond, Ann, primary, and Burow, Matthew E., primary

Published
2023
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50. Supplementary Figures 1-18 from Sorafenib Enhances Pemetrexed Cytotoxicity through an Autophagy-Dependent Mechanism in Cancer Cells

Author

Bareford, M. Danielle, primary, Park, Margaret A., primary, Yacoub, Adly, primary, Hamed, Hossein A., primary, Tang, Yong, primary, Cruickshanks, Nichola, primary, Eulitt, Patrick, primary, Hubbard, Nisan, primary, Tye, Gary, primary, Burow, Matthew E., primary, Fisher, Paul B., primary, Moran, Richard G., primary, Nephew, Kenneth P., primary, Grant, Steven, primary, and Dent, Paul, primary

Published
2023
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