Ubiquitin-proteasomal degradation of antiapoptotic survivin facilitates induction of apoptosis in prostate cancer cells by pristimerin

Abstract

Pristimerin (PM), a quinonemethide triterpenoid, is a promising anticancer agent with potent antiproliferative and apoptosis-inducing activities against cancer cell lines. However, the anticancer activity and mechanisms of PM in prostate cancer cells have not been adequately investigated. Here we report that the degradation of survivin plays an important role in the antiproliferative and proapoptotic effects of PM in carcinoma of the prostate (CaP) cell lines. Treatment with PM inhibited proliferation and induced apoptosis in LNCaP and PC-3 cells as characterized by the loss of cell viability and an increase in Annexin V-binding and cleavage of PARP-1, respectively. The antiproliferative and apoptosis-inducing effects of PM were associated with the inhibition of cell cycle regulatory proteins, antiapoptotic survivin and members of the Bcl-2 family. Data showed that response to PM is regulated by survivin since overexpression of survivin rendered CaP cells resistant to PM. Furthermore, downregulation of survivin by PM was mediated through the ubiquitin-proteasomal degradation. Together, these data demonstrate that pristimerin inhibits proliferation and induces apoptosis in CaP cells by abolishing survivin through the ubiquitin-proteasome pathway.

Pristimerin overcomes adriamycin resistance in breast cancer cells through suppressing Akt signaling

“…In addition, it has been reported that pristimerin has promising clinical potential as both a therapeutic and chemopreventive agent for various types of cancer such as pancreatic cancer, glioma, leukemia, cervical cancer, prostate cancer and breast cancer (6)(7)(8)(9)(10)(11). Pristimerin has been shown to induce cell death via a number of several mechanisms, including proteosome inhibition, caspase activation, inhibition of cell cycle progression, and suppression of antiapoptotic nuclear factor kappa B (NF-κB) and Akt signaling pathways (6,9).…”

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.…”

Pristimerin effectively inhibits the malignant phenotypes of uveal melanoma cells by targeting NF-κB pathway

“…* P<0.05, ** P<0.01, one-way ANOVA was used for statistical analysis. and the anti-apoptotic role of survivin in pristimerin-inducing apoptosis in prostate cancer cells (38), we hypothesized that survivin might be critical in pristimerin-inducing apoptosis in UM cells. The Omm 1 cell ectopic overexpression of survivin by lentiviral construct encoding survivin were more resistant to pristimerin than cells transfected with empty vector (Fig.…”