Celastrol inhibits tumor cell proliferation and promotes apoptosis through the activation of c-Jun N-terminal kinase and suppression of PI3 K/Akt signaling pathways

Abstract

Celastrol, a plant triterpene has attracted great interest recently, especially for its potential anti-inflammatory and anti-cancer activities. In the present report, we investigated the effect of celastrol on proliferation of various cancer cell lines. The mechanism, by which this triterpene exerts its apoptotic effects, was also examined in detail. We found that celastrol inhibited the proliferation of wide variety of human tumor cell types including multiple myeloma, hepatocellular carcinoma, gastric cancer, prostate cancer, renal cell carcinoma, head and neck carcinoma, non-small cell lung carcinoma, melanoma, glioma, and breast cancer with concentrations as low as 1 μM. Growth inhibitory effects of celastrol correlated with a decrease in the levels of cyclin D1 and cyclin E, but concomitant increase in the levels of p21 and p27. The apoptosis induced by celastrol was indicated by the activation of caspase-8, bid cleavage, caspase-9 activation, caspase-3 activation, PARP cleavage and through the down regulation of anti-apoptototic proteins. The apoptotic effects of celastrol were preceded by activation of JNK and down-regulation of Akt activation. JNK was needed for celastrol-induced apoptosis, and inhibition of JNK by pharmacological inhibitor abolished the apoptotic effects. Overall, our results indicate that celastrol can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and down-regulation of anti-apoptotic protein expression.

Celastrol Suppresses Growth and Induces Apoptosis of Human Hepatocellular Carcinoma through the Modulation of STAT3/JAK2 Signaling Cascade In Vitro and In Vivo

“…Celastrol has been found to inhibit the proliferation, induce apoptosis, and suppress invasion/migration and angiogenesis in a wide variety of tumor models both in vitro and in vivo (16)(17)(18). The efficacy of celastrol to modulate the expression of various key mediators of tumorigenesis such as proinflammatory cytokines, adhesion molecules, potassium channels, NF-kB, TGF-activated kinase 1 (TAK1), CXCR4, VEGF receptor (VEGFR), STAT3, proteasome, and heat shock response has been reported previously (14,17,(19)(20)(21)(22)(23)(24)(25). However, the potential anticancer effects of celastrol and its mechanism of action(s) have never been investigated before in HCCs, which is one of the most lethal cancers.…”

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

“…This triterpene has also been shown to directly target Cys-179 in the activation loop of IKK-b kinase and also modulate the expression of proteins with cell survival (IAP1, XIAP, Bcl-2, Bcl-xL, cFLIP, survivin), cell proliferation (cyclin D1, COX-2), angiogenic, and metastatic (MMP-9, ICAM-1, VEGF) activities in tumor cells [83,96]. We have also recently demonstrated that celastrol can indeed potentiate the apoptotic effects of botezomib and thalidomide by suppression of both NF-jB and STAT3 activation in multiple myeloma cells [92]. Celastrol up-regulates death receptor 4 (DR4) and 5 (DR5) expression at mRNA, and cell surface receptor levels, and knockdown of DR4 or DR5 attenuates the PARP cleavage caused by the combination of celastrol and TRAIL/Apo-2L, denoting the critical roles of DR induction in this sensitization of cells to apoptosis [91].…”

“…This triterpene has also been found to suppress tumor initiation, promotion and metastasis in various cancer models through modulation of multiple pro-inflammatory cytokines, chemokines, enzymes and transcription factors [4,[86][87][88][89][90][91]. For example, celastrol has been shown to inhibit the proliferation of a wide variety of tumor cells [6,83,[92][93][94]. Studies to define its therapeutic mechanism showed that it can suppress the NF-jB signaling pathway [83,95], VEGFR expression [96], inhibit AKT/mTOR pathway [87], suppresses Bcr/Abl and induce apoptosis in imatinib resistant chronic leukemia cells [97], inhibit heat shock protein (HSP) 90 [98,99], ERK [100], proteasomes [93,101] and activate caspase8 [102].…”

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

“…18,19 Consequently, loss of cyclin E evoked by ZA might be important (at least partially) for diminishing the growth capacity of the tumor cells. No data are available dealing with the influence of ZA on cyclin E in PC.…”