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The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279402/ https://www.ncbi.nlm.nih.gov/pubmed/25296977 |
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author | Ringer, Lymor Sirajuddin, Paul Tricoli, Lucas Waye, Sarah Choudhry, Muhammad Umer Parasido, Erika Sivakumar, Angiela Heckler, Mary Naeem, Aisha Abdelgawad, Iman Liu, Xuefeng Feldman, Adam S. Lee, Richard J. Wu, Chin-Lee Yenugonda, Venkata Kallakury, Bhaskar Dritschilo, Anatoly Lynch, John Schlegel, Richard Rodriguez, Olga Pestell, Richard G. Avantaggiati, Maria Laura Albanese, Chris |
author_facet | Ringer, Lymor Sirajuddin, Paul Tricoli, Lucas Waye, Sarah Choudhry, Muhammad Umer Parasido, Erika Sivakumar, Angiela Heckler, Mary Naeem, Aisha Abdelgawad, Iman Liu, Xuefeng Feldman, Adam S. Lee, Richard J. Wu, Chin-Lee Yenugonda, Venkata Kallakury, Bhaskar Dritschilo, Anatoly Lynch, John Schlegel, Richard Rodriguez, Olga Pestell, Richard G. Avantaggiati, Maria Laura Albanese, Chris |
author_sort | Ringer, Lymor |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4279402 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-42794022015-01-06 The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells Ringer, Lymor Sirajuddin, Paul Tricoli, Lucas Waye, Sarah Choudhry, Muhammad Umer Parasido, Erika Sivakumar, Angiela Heckler, Mary Naeem, Aisha Abdelgawad, Iman Liu, Xuefeng Feldman, Adam S. Lee, Richard J. Wu, Chin-Lee Yenugonda, Venkata Kallakury, Bhaskar Dritschilo, Anatoly Lynch, John Schlegel, Richard Rodriguez, Olga Pestell, Richard G. Avantaggiati, Maria Laura Albanese, Chris Oncotarget Research Paper 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. Impact Journals LLC 2014-09-26 /pmc/articles/PMC4279402/ /pubmed/25296977 Text en Copyright: © 2014 Ringer et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Ringer, Lymor Sirajuddin, Paul Tricoli, Lucas Waye, Sarah Choudhry, Muhammad Umer Parasido, Erika Sivakumar, Angiela Heckler, Mary Naeem, Aisha Abdelgawad, Iman Liu, Xuefeng Feldman, Adam S. Lee, Richard J. Wu, Chin-Lee Yenugonda, Venkata Kallakury, Bhaskar Dritschilo, Anatoly Lynch, John Schlegel, Richard Rodriguez, Olga Pestell, Richard G. Avantaggiati, Maria Laura Albanese, Chris The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells |
title | The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells |
title_full | The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells |
title_fullStr | The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells |
title_full_unstemmed | The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells |
title_short | The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells |
title_sort | induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279402/ https://www.ncbi.nlm.nih.gov/pubmed/25296977 |
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