title: Pristimerin Induces Apoptosis in Prostate Cancer Cells by Down-regulating Bcl-2 through ROS-dependent Ubiquitin-proteasomal Degradation Pathway.
abstract: Pristimerin is a quinonemethide triterpenoid with the potential of a promising anticancer agent. Pristimerin (PM) has shown anticancer activity against a range of cancer cell lines, but its activity for prostate cancer has not been adequately investigated. In the present study we have examined the underlying mechanisms of the apoptotic response of the hormone-sensitive (LNCaP) and hormone-refractory (PC-3) prostate cancer cell lines to PM. Treatment with PM induced apoptosis in both cell lines as characterized by increased annexin V-binding and cleavage of PARP-1 and procaspases-3 and -9. It also induced mitochondrial depolarization, cytochrome c release from mitochondria and generation of reactive oxygen species (ROS). Response to PM is regulated by Bcl-2 since it down-regulated Bcl-2 expression and overexpression of Bcl-2 rendered prostate cancer cells resistant to PM. ROS plays a role in down-regulation of Bcl-2, since treatment with PM in the presence of various ROS modulators, e.g., n-acetylcysteine (NAC), a general purpose antioxidant; diphenylene iodonium (DPI), a NADPH inhibitor; rotenone (ROT), a mitochondrial electron transport chain interrupter rotenone or MnTBAP, a O2scavenger, attenuated the down-regulation of Bcl-2. Furthermore, ROS is also involved in the ubiquitination and proteasomal degradation of Bcl-2 as both of these events were blocked by O2-scavenger MnTBAP. Thus, pristimerin induces apoptosis in prostate cancer cells predominately through the mitochondrial apoptotic pathway by inhibiting antiapoptic Bcl-2 through a ROS-dependent ubiquitin-proteasomal degradation pathway.
authors.affiliation: Departments of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Yong Bo
authors.initials: YB
authors.lastname: Liu
authors.affiliation: Departments of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gao
authors.affiliation: Departments of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Dorrah
authors.initials: D
authors.lastname: Deeb
authors.affiliation: Department of Radiology, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Ali S
authors.initials: AS
authors.lastname: Arbab
authors.affiliation: Departments of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Gautam
keywords: Apoptosis; Bcl-2; Pristimerin; Proteasomes; ROS; Ubiquitin