NVP-BEZ235, a dual PI3K/mTOR inhibitor, induces cell death through alternate routes in prostate cancer cells depending on the PTEN genotype.

Abstract

Deregulation of the PI3K-AKT/mTOR pathway due to mutation of the tumor suppressor gene PTEN frequently occurs in human prostate cancer and is therefore considered to be an attractive therapeutic target. Here, we investigated how the PTEN genotype affected the antitumor effect of NVP-BEZ235 in human prostate cancer cells. In this setting, NVP-BEZ235 induced cell death in a PTEN-independent manner. NVP-BEZ235 selectively induced apoptotic cell death in the prostate cancer cell line DU145, which harbors wild-type PTEN; however, in the PC3 cell line, which is PTEN-null, treatment with NVP-BEZ235 resulted in autophagic cell death. Consistently, NVP-BEZ235 treatment did not result in the cleavage of caspase-3; instead, it resulted in the conversion of LC3-I to LC3-II, indicating autophagic cell death; these results suggest that an alternate mechanism of cell death is induced by NVP-BEZ235 in PTEN-null prostate cancer cells. Based on our findings, we conclude that the PTEN/PI3K/Akt pathway is critical for prostate cancer survival, and targeting PI3K signaling by NVP-BEZ235 may be beneficial in the treatment of prostate cancer, independent of the PTEN genotype.

• Authors: Seung-Woo Hong, Jae-Sik Shin, Jai-Hee Moon, Ye-Seul Kim, Jooyoung Lee, Eun Kyoung Choi, Seung-Hee Ha, Dae Hee Lee, Ha Na Chung, Jeong Eun Kim, Kyu-Pyo Kim, Yong Sang Hong, Jae-Lyun Lee, Wang-Jae Lee, Eun Kyung Choi, Jung Shin Lee, Dong-Hoon Jin, Tae Won Kim
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 19 Issue 5 Pg. 895-904 (May 2014) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 24652480 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Phosphoinositide-3 Kinase Inhibitors
• Quinolines
• MTOR protein, human
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• PTEN protein, human
• dactolisib

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Genotype
• Humans
• Imidazoles (pharmacology)
• Male
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Prostatic Neoplasms (metabolism, pathology)
• Quinolines (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)