Oncotarget

Research Papers:

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, Paul Sirajuddin, Lucas Tricoli, Sarah Waye, Muhammad Umer Choudhry, Erika Parasido, Angiela Sivakumar, Mary Heckler, Aisha Naeem, Iman Abdelgawad, Xuefeng Liu, Adam S. Feldman, Richard J. Lee, Chin-Lee Wu, Venkata Yenugonda, Bhaskar Kallakury, Anatoly Dritschilo, John Lynch, Richard Schlegel, Olga Rodriguez, Richard G. Pestell, Maria Laura Avantaggiati and Chris Albanese _

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Oncotarget. 2014; 5:10678-10691. https://doi.org/10.18632/oncotarget.2528

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Abstract

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

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.


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