Reactive Oxygen Species-Dependent Activation of Bax and Poly(ADP-ribose) Polymerase-1 Is Required for Mitochondrial Cell Death Induced by Triterpenoid Pristimerin in Human Cervical Cancer Cells

Abstract

Naturally occurring triterpenoid compounds have long been used as anti-inflammatory, antimalarial, and insecticidal agents. It has become evident that some of the natural or synthetic triterpenoids have promising clinical potential as both a therapeutic and chemopreventive agent for cancer. However, the molecular basis for the antitumor activity of triterpenoid has yet to be defined. In this study, we show that pristimerin, a natural triterpenoid, induces mitochondrial cell death in human cervical cancer cells and that reactive oxygen species (ROS)-dependent activation of both Bax and poly(ADP-ribose) polymerase-1 (PARP-1) is critically required for the mitochondrial dysfunction. We also showed that c-Jun N-terminal kinase (JNK) is involved in ROS-dependent Bax activation. Treatment of pristimerin induced an increase in intracellular ROS, JNK activation, conformational change, and mitochondrial redistribution of Bax, mitochondrial membrane potential loss, and cell death. The PARP-1 was also found to be activated by pristimerin treatment. An antioxidant, N-acetyl-L-cysteine (NAC), inhibited pristimerin-induced JNK activation, Bax relocalization, and PARP-1 activation, as well as mitochondrial cell death. Moreover, inhibition of JNK clearly suppressed conformational change and mitochondrial translocation of Bax and subsequent mitochondrial cell death but did not affect PARP-1 activation. Inhibition of PARP-1 with 1,5-dihydroxyisoquinoline (DIQ) or with small interfering RNA of PARP-1 significantly attenuated pristimerininduced mitochondrial membrane potential loss and cell death but did not affect JNK activation and Bax relocalization. These results indicate that the natural triterpenoid pristimerin induces mitochondrial cell death through ROS-dependent activation of both Bax and PARP-1 in human cervical cancer cells and that JNK is involved in ROS-dependent Bax activation.

Pristimerin Inhibits Breast Cancer Cell Migration by Up-regulating Regulator of G Protein Signaling 4 Expression

“…The redundant metastatic signals by different activated GPCRs simultaneously drive the migration of breast cancer cells, which makes the inhibition of breast cancer metastasis by a GPCR-specific inhibitor unfeasible. Ideally, simultaneous 1 can inhibit tumor cell proliferation by inhibiting the NF-κB pathway and cell cycling (Boire et al, 2005;Costa et al, 2008;Yang et al, 2008;Byun et al, 2009;Tiedemann et al, 2009). In addition, prestimerin has been reported to induce caspase-dependent apoptosis of breast cancer cells (Wu et al, 2005) and prostate cancer cells in vitro (Yang et al, 2008).…”

HCV upregulates Bim through the ROS/JNK signalling pathway, leading to Bax-mediated apoptosis

“…However, the exact mechanism of HCV-induced Bax activation remained to be elucidated. Meanwhile, a possible link between ROS and Bax activation has been reported (Buccellato et al, 2004;Byun et al, 2009;D'Alessio et al, 2005;Nie et al, 2008). Increasing evidence has suggested that c-Jun NH 2 -terminal kinase (JNK) plays a role in Bax-mediated apoptosis by regulating the function of Bim (Lei & Davis, 2003;Okuno et al, 2004;Putcha et al, 2003).…”

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). In breast cancer, it has been reported that pristimeirin induces apoptotic cell death in MDA-MB-231 breast cancer cells in a caspase-dependent manner (11).…”