The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells.

// Lymor Ringer 1,* , Paul Sirajuddin 1,* , Lucas Tricoli 1,* , Sarah Waye 1 , Muhammad Umer Choudhry 1 , Erika Parasido 1 , Angiela Sivakumar 1 , Mary Heckler 1 , Aisha Naeem 1 , Iman Abdelgawad 1,6 , Xuefeng Liu 2 , Adam S. Feldman 3 , Richard J. Lee 3 , Chin-Lee Wu 3 , Venkata Yenugonda 1 , Bhaskar Kallakury 2 , Anatoly Dritschilo 4 , John Lynch 4 , Richard Schlegel 1,2 , Olga Rodriguez 1 , Richard G. Pestell 5 , Maria Laura Avantaggiati 1,* and Chris Albanese 1,2,* 1 Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 2 Department of Pathology, Georgetown University Medical Center, Washington, DC, USA 3 Massachusetts General Hospital, Boston, USA 4 Georgetown University Hospital, Washington, DC, USA 5 Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 6 National Cancer Institute of Egypt, Cairo, Egypt * These authors contributed equally to this work Correspondence: Chris Albanese, email: // Keywords : p53, apoptosis, autophagy, primary cells, prostate Received : July 14, 2014 Accepted : September 25, 2014 Published : September 26, 2014 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.