Authors

Lymor Ringer, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Paul Sirajuddin, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Lucas Tricoli, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Sarah Waye, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Muhammad Umer Choudhry, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Erika Parasido, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Angiela Sivakumar, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Mary Heckler, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Aisha Naeem, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Iman Abdelgawad, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; National Cancer Institute of Egypt
Xuefeng Liu, Department of Pathology, Georgetown University Medical Center
Adam S Feldman, Massachusetts General Hospital
Richard J Lee, Massachusetts General Hospital
Chin-Lee Wu, Massachusetts General Hospital
Venkata Yenugonda, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Bhaskar Kallakury, Department of Pathology, Georgetown University Medical Center
Anatoly Dritschilo, Georgetown University Hospital
John Lynch, Georgetown University Hospital
Richard Schlegel, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Department of Pathology, Georgetown University Medical Center
Olga Rodriguez, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Richard Pestell, Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Maria Laura Avantaggiati, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center
Chris Albanese, Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center; Department of Pathology, Georgetown University Medical Center

Document Type

Article

Publication Date

11-15-2014

Comments

This article has been peer reviewed. It was published in: Oncotarget.

Volume 5, Issue 21, 2014, Pages 10678-10691.

The published version is available at PMID: 25296977

Copyright © © 2014 Ringer et al.

Abstract

The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; we have defined the mechanisms of VMY-induced prostate cancer cell death. Herein, we show that the cytotoxic effects of VMY required a p53-dependent induction of autophagy, and that inhibition of autophagy abrogated VMY-induced cell death. Cancer cell lines harboring p53 missense mutations evaded VMY toxicity and treatment with a small molecule compound that restores p53 activity re-established VMY-induced cell death. The elucidation of the molecular mechanisms governing VMY-dependent cell death in cell lines, and importantly in CRCs, provides the rationale for clinical studies of VMY, alone or in combination with p53 reactivating compounds, in human prostate cancer.

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