The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells

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.

Rottlerin-induced autophagy leads to apoptosis in bladder cancer cells

“…For instance, atorvastatin is considered by some to cause autophagy to promote apoptosis in human prostate cancer cells (33), whilst others have a contrasting views, and consider that inhibition of autophagy potentiates atorvastatin-induced apoptotic cell death (34). Although there is known crosstalk between autophagy and apoptosis, since they share certain signaling pathways and proteins, the mechanism where this bridging occurs has not been fully defined (35). In the present study autophagy was induced by rottlerin, as indicated by a number of observations.…”

Targeting Programmed Cell Death Using Small‐Molecule Compounds to Improve Potential Cancer Therapy

“…For instance, fangchinoline induces autophagic cell death through the p53/Sestrin2/AMPK signaling in PLC/PRF/5 and HepG2 cells . VMY‐1‐103 is a dansylated analog of purvalanol B and is also reported to have a remarkable antitumor activity through p53‐dependent autophagy in prostate cancer cells . Paclitaxel triggers autophagic cell death with increased p53 expression before LC3B regulation in various cancers, such as glioma, colon cancer, and prostate cancer cells …”

A Rapid Filter Insert-based 3D Culture System for Primary Prostate Cell Differentiation

“…For example, reformulated differentiation medias that may better promote luminal vs basal differentiation can be rapidly tested. Since lentiviral infection of CRCs has been performed as easily as with commercial cancer cells 7 and the 2D CRCs have also been transfected with CAS9/CRISPR gene editing technology vectors to permanently modify the cell genome (data not shown), the effect of mutated, deleted or repaired genes can be tested. Similarly, lineage tracking can be made possible by introducing lineage specific reporter genes.…”

“…Note: CM is F-media conditioned by irradiated J2 cells and contains 10 μm Y-27632 as previously described 7,8,9,11 .…”

“…Conversely, basal cells are localized beneath the luminal layer and express cytokeratin 5 and p63, but low levels of the AR 5 . We 7,8,9 and others 10 have successfully used prostate CRCs in preclinical mechanistic drug sensitivity investigations. However, when grown under standard 2D tissue culture conditions, these cells fail to fully engage AR signaling 10 .…”