Document Type
Article
Publication Date
11-15-2014
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.
Recommended Citation
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; Avantaggiati, Maria Laura; and 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." (2014). Kimmel Cancer Center Faculty Papers. Paper 47.
https://jdc.jefferson.edu/kimmelccfp/47
PubMed ID
25296977
Comments
This article has been peer reviewed. It was published in: Oncotarget.
Volume 5, Issue 21, 2014, Pages 10678-10691.
The published version is available at PMID: 25296977
Copyright © © 2014 Ringer et al.