The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells
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Lymor Ringer1,*, Paul Sirajuddin1,*, Lucas Tricoli1,*, Sarah Waye1, Muhammad Umer Choudhry1, Erika Parasido1, Angiela Sivakumar1, Mary Heckler1, Aisha Naeem1, Iman Abdelgawad1,6, Xuefeng Liu2, Adam S. Feldman3, Richard J. Lee3, Chin-Lee Wu3, Venkata Yenugonda1, Bhaskar Kallakury2, Anatoly Dritschilo4, John Lynch4, Richard Schlegel1,2, Olga Rodriguez1, Richard G. Pestell5, Maria Laura Avantaggiati1,* and Chris Albanese1,2,*
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
Chris Albanese, email:
Keywords: p53, apoptosis, autophagy, primary cells, prostate
Received: July 14, 2014 Accepted: September 25, 2014 Published: September 26, 2014
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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