title: 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.affiliation: Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.
authors.forename: Seung-Woo
authors.initials: SW
authors.lastname: Hong
authors.forename: Jae-Sik
authors.initials: JS
authors.lastname: Shin
authors.forename: Jai-Hee
authors.initials: JH
authors.lastname: Moon
authors.forename: Ye-Seul
authors.initials: YS
authors.lastname: Kim
authors.forename: Jooyoung
authors.initials: J
authors.lastname: Lee
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Choi
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Ha
authors.forename: Dae Hee
authors.initials: DH
authors.lastname: Lee
authors.forename: Ha Na
authors.initials: HN
authors.lastname: Chung
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Kyu-Pyo
authors.initials: KP
authors.lastname: Kim
authors.forename: Yong Sang
authors.initials: YS
authors.lastname: Hong
authors.forename: Jae-Lyun
authors.initials: JL
authors.lastname: Lee
authors.forename: Wang-Jae
authors.initials: WJ
authors.lastname: Lee
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005838:Genotype; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011804:Quinolines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494929:PTEN protein, human; C531198:dactolisib