The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells
| Autor: | Paul Sirajuddin, Muhammad Umer Choudhry, Erika Parasido, Angiela Sivakumar, Lymor Ringer, Venkata Mahidhar Yenugonda, Iman Abdelgawad, Maria Laura Avantaggiati, Olga Rodriguez, Bhaskar Kallakury, Richard T. Lee, Adam S. Feldman, Chris Albanese, John H. Lynch, Sarah Waye, Mary M. Heckler, Anatoly Dritschilo, Richard G. Pestell, Aisha Naeem, Xuefeng Liu, Lucas Tricoli, Richard Schlegel, Chin-Lee Wu |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
p53
Male Programmed cell death autophagy Cell cycle checkpoint Blotting Western primary cells Biology 03 medical and health sciences Prostate cancer 0302 clinical medicine Proton transport medicine Tumor Cells Cultured Humans 030304 developmental biology Cell Proliferation Dansyl Compounds 0303 health sciences prostate Cell growth Adenine Autophagy apoptosis Cancer Prostatic Neoplasms medicine.disease Flow Cytometry 3. Good health Oncology 030220 oncology & carcinogenesis Cancer cell Mutation Cancer research Tumor Suppressor Protein p53 Research Paper Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // 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. |
| Databáze: | OpenAIRE |
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