Pristimerin Induces Apoptosis in Prostate Cancer Cells by Downregulating 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 O2 scavenger, 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 O 2− 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.

Induction of cell cycle arrest and apoptosis by betulinic acid-rich fraction from Dillenia suffruticosa root in MCF-7 cells involved p53/p21 and mitochondrial signalling pathway

“…It was noted that the increase in Bax/Bcl-2 ratio was mainly due to the down-regulation of Bcl-2 at protein level, but not at the mRNA level. Thus, it is suggested that Bcl-2 protein is posttranslationally modified by either phosphorylation or ubiquitination via MAPKs and AKT, resulting in a proteosomal degradation of Bcl-2 protein which increases the BAX/BCL-2 ratio to initiate the mitochondrial apoptotic pathway (Deeb et al, 2014;Liu et al, 2013;Gao and Dou, 2000).…”

Antioxidative CXXC Peptide Motif From Mesencephalic Astrocyte-Derived Neurotrophic Factor Antagonizes Programmed Cell Death

“…We show that activation of both caspase-8 and caspases 3/7 by Fas-activating antibody is impeded by the CKGC peptide. ROS can inactivate anti-apoptotic Bcl-2 and prevent procaspase-3 processing ( Liu et al, 2013 ; Martinez-Reyes and Cuezva, 2014 ). Also, excessive ROS leads to down-regulation of c-FLIP, the inhibitor of caspase-8 ( Circu and Aw, 2010 ; Wilkie-Grantham et al, 2013 ).…”

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

“…The antiproliferative activity of pristimerin goes beyond colon-related cancers, it is extended to breast [346][347][348][349][350], melanomas [351], osteosarcoma [352], pancreatic [353,354], and prostate cancers [355][356][357][358]. Herein, we describe a few examples focusing on articles that have demonstrated potential mechanisms of action.…”

“…Its progression was reported to be prevented by pristimerin-induced inhibition on HIF-1α and SPHK-1, which stimulates different cellular processes including cell proliferation, cell survival, and angiogenesis [355,369]. Pristimerin also induced apoptosis of prostate cancer cells through activation of mitochondrial apoptotic pathway [358], ubiquitin-proteasomal degradation [357], and inhibition of proteasomal chymotrypsin-like activity (a complex associated with cell proliferation, apoptosis, and cancer progression) [370,371]. These summarized findings provide evidences regarding pristimerin antiproliferative and cytotoxic activity as well as clinical benefits for treatment of different types of cancer.…”