Sorafenib Sensitizes (−)-Gossypol-Induced Growth Suppression in Androgen-Independent Prostate Cancer Cells via Mcl-1 Inhibition and Bak Activation

Abstract

The natural BH3-mimetic (À)-gossypol shows promising efficacy in ongoing phase II/III clinical trials for human prostate cancer. Here, we show for the first time, that treatment with (À)-gossypol and multikinase inhibitor sorafenib synergistically suppresses the growth of androgen-independent prostate cancer cells (AI-PC) in vitro and in vivo. Our data suggest that sorafenib attenuates (À)-gossypol-induced Mcl-1 upregulation in AI-PCs. In this way, it serves as a potent chemosensitizer to affect cell death. Interestingly, (À)-gossypol and sorafenib induce cell death via two distinct pathways among different AI-PCs; DU145 cells via apoptosis and PC-3 via autophagy. The appointed death pathway may depend on the level of proapoptotic protein Bak, although the level of antiapoptotic protein Bcl-2 plays some role in it. DU145 cells with high Bak level prefer apoptosis induction, whereas PC-3 cells with low Bak prefer the induction of autophagy. Furthermore, inhibiting nondominant death pathways, that is, autophagy in DU145 and apoptosis in PC-3, enhances cell killing by (À)-gossypol/sorafenib combination therapy. Ultimately, our data expose a new action for sorafenib as an enhancer of (À)-gossypol-induced cell growth suppression and reveal a novel cell death mode by Bak activation manners in AI-PCs. These new insights may facilitate the rational design of clinical trials by selecting patients most likely to benefit from the Bcl-2-targeted molecular therapy. Mol Cancer Ther; 11(2); 416-26. Ó2011 AACR.

The role of STAT3 in autophagy

“…A wide range of RTKs phosphorylate STAT3 directly or via SRC kinase, and several studies have proven that blocking kinases such as KDR, PDGFRB, and ALK results in enhanced autophagy by subsequent inhibition of the STAT3 pathway (Table 3). 14,41,42,50,[74][75][76][77][78][79][80][81][82][83] Currently, several JAK-STAT inhibitors are being examined in clinical trials for cancer therapy. For example, in a phase II clinical trial to treat metastatic pancreatic cancer, ruxolitinib together with capecitabine showed a benefit for overall survival and progression-free survival compared with a placebo plus capecitabine used in second-line therapy, promoting the application of JAK-STAT inhibitors in cancer therapy.…”

Valproic acid exposure sequentially activates Wnt and mTOR pathways in rats

“…Protein concentrations were measured using a BCA kit. Immunoblotting analysis was performed as described previously (Lian et al, 2012). Antibodies against phospho-or total ERK1/2, phospho-or total AKT, phospho-or total GSK3beta, phospho-or total mTOR, phospho-or total S6 kinase, Atg5, Atg10, β-catenin and LC3 were purchased from Cell Signaling Technology; GAPDH and Beclin1 were from Santa Cruz Biotechnology.…”

“…Preparation of ultrathin sections was described previously (Lian et al, 2012). Briefly, rats were perfused and postfixed in 1% osmium tetroxide with 0.1% potassium ferricyanide.…”

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

“…Tumor tissues were processed for western blot as described previously. 42 All animal experiments were carried out according to the protocol approved by the Third Military Medical University Guidelines for Use and Care of Animals.…”