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8 results on '"Michael C. Nicastri"'

2. Chemical Methods from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

Author

Ravi K. Amaravadi, Jeffrey D. Winkler, David W. Speicher, Donita C. Brady, Roberto Zoncu, Meenhard Herlyn, Xiaowei Xu, Shujing Liu, Qin Liu, Ronen Marmorstein, Joshua Rabinowitz, Yiling Lu, Gordon B. Mills, Maureen E. Murphy, Julie S. Barber-Rotenberg, Zhi Wei, Samuel M. Levi, Rani Ojha, Sengottuvelan Murugan, Shengfu Piao, Gretchen M. Alicea, Gao Zhang, Cynthia I. Chude, Eric Witze, Chun-Yan Lim, Michel Nofal, Amruta Ronghe, Quentin McAfee, Colin Fennelly, Noel McLaughlin, Michael C. Nicastri, and Vito W. Rebecca

Abstract

Supplemental Chemical Methods

Published
2023

3. Supplemental Figures S1-S7 and Supplemental Table S1 from A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

Author

Ravi K. Amaravadi, Jeffrey D. Winkler, David W. Speicher, Donita C. Brady, Roberto Zoncu, Meenhard Herlyn, Xiaowei Xu, Shujing Liu, Qin Liu, Ronen Marmorstein, Joshua Rabinowitz, Yiling Lu, Gordon B. Mills, Maureen E. Murphy, Julie S. Barber-Rotenberg, Zhi Wei, Samuel M. Levi, Rani Ojha, Sengottuvelan Murugan, Shengfu Piao, Gretchen M. Alicea, Gao Zhang, Cynthia I. Chude, Eric Witze, Chun-Yan Lim, Michel Nofal, Amruta Ronghe, Quentin McAfee, Colin Fennelly, Noel McLaughlin, Michael C. Nicastri, and Vito W. Rebecca

Abstract

Supplemental Figures and Table

Published
2023

4. Supplementary Figures S1-S4 from PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer

Author

Ravi K. Amaravadi, Jeffrey D. Winkler, David W. Speicher, Phyllis A. Gimotty, Ronen Marmorstein, Meenhard Herlyn, Xiaowei Xu, Lynn M. Schuchter, Jennifer J. Lee, Gretchen M. Alicea, Alessandra Martorella, Estela Noguera-Ortega, Shengfu Piao, Rani Ojha, Aaron R. Goldman, Gao Zhang, Noel P. McLaughlin, Quentin McAfee, Amruta Ronghe, Julie S. Barber-Rotenberg, Cynthia I. Chude, Colin Fennelly, Michael C. Nicastri, and Vito W. Rebecca

Abstract

Supplementary Figures S1-S4

Published
2023

5. Chemical Methods from PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer

Author

Ravi K. Amaravadi, Jeffrey D. Winkler, David W. Speicher, Phyllis A. Gimotty, Ronen Marmorstein, Meenhard Herlyn, Xiaowei Xu, Lynn M. Schuchter, Jennifer J. Lee, Gretchen M. Alicea, Alessandra Martorella, Estela Noguera-Ortega, Shengfu Piao, Rani Ojha, Aaron R. Goldman, Gao Zhang, Noel P. McLaughlin, Quentin McAfee, Amruta Ronghe, Julie S. Barber-Rotenberg, Cynthia I. Chude, Colin Fennelly, Michael C. Nicastri, and Vito W. Rebecca

Abstract

Chemical Methods

Published
2023

6. Data from PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer

Author

Ravi K. Amaravadi, Jeffrey D. Winkler, David W. Speicher, Phyllis A. Gimotty, Ronen Marmorstein, Meenhard Herlyn, Xiaowei Xu, Lynn M. Schuchter, Jennifer J. Lee, Gretchen M. Alicea, Alessandra Martorella, Estela Noguera-Ortega, Shengfu Piao, Rani Ojha, Aaron R. Goldman, Gao Zhang, Noel P. McLaughlin, Quentin McAfee, Amruta Ronghe, Julie S. Barber-Rotenberg, Cynthia I. Chude, Colin Fennelly, Michael C. Nicastri, and Vito W. Rebecca

Abstract

Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here, we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than hydroxychloroquine (HCQ). Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR/Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives.Significance:This study identifies PPT1 as the previously unknown lysosomal molecular target of monomeric and dimeric CQ derivatives. Genetic suppression of PPT1 impairs tumor growth, and PPT1 levels are elevated in cancer and associated with poor survival. These findings provide a strong rationale for targeting PPT1 in cancer.This article is highlighted in the In This Issue feature, p. 151

Published
2023

7. Figure S1-4, TABLES1, S2 from ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma

Author

Ashani T. Weeraratna, Maureen E. Murphy, Ravi K. Amaravadi, Maria S. Soengas, Jeffrey D. Winkler, Michael C. Nicastri, Meenhard Herlyn, Hong Wu, Xiaowei Xu, Gordon B. Mills, Michael A. Davies, Y.N. Vashisht Gopal, Qin Liu, Patricia A. Brafford, Ling Li, Vito W. Rebecca, Reeti Behera, Amanpreet Kaur, Marie R. Webster, Curtis H. Kugel, Anna Budina-Kolomets, and Abibatou Ndoye

Abstract

Figure S1: Wnt5A expression correlates with high autophagy in melanoma. Figure S2: Wnt5A increases autophagy in melanoma Figure S3: ATG5 affects Wnt signaling in melanoma Figure S4: β-catenin increases the sensitivity of melanoma cells to autophagy inhibition Supplemental Figure Legends SUPPLEMENTAL TABLE 1: DENSITOMETRY FOR ALL WESTERNS Supplemental Table 2. Tissue microarrays (TMA) H scores

Published
2023

8. Data from ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma

Author

Ashani T. Weeraratna, Maureen E. Murphy, Ravi K. Amaravadi, Maria S. Soengas, Jeffrey D. Winkler, Michael C. Nicastri, Meenhard Herlyn, Hong Wu, Xiaowei Xu, Gordon B. Mills, Michael A. Davies, Y.N. Vashisht Gopal, Qin Liu, Patricia A. Brafford, Ling Li, Vito W. Rebecca, Reeti Behera, Amanpreet Kaur, Marie R. Webster, Curtis H. Kugel, Anna Budina-Kolomets, and Abibatou Ndoye

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 Wnt5Ahigh 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.

Published
2023

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