Anticancer efficacy of deguelin in human prostate cancer cells targeting glycogen synthase kinase‐3 β/β‐catenin pathway

Abstract

Activation of survival pathways has been associated with chemoresistance and progression of androgen independence which places a major obstacle to successful treatment of metastatic prostate cancer. Deguelin, a rotenoid isolated from Mundulea sericea, has an anticancer effect against several types of cancers; however, the mechanism of its antitumor effects on prostate cancer is not well understood. The aim of our study was to elucidate the effect of deguelin on the growth of prostate cancer cells and its putative mechanism of action. Deguelin decreased the viability of both androgen-dependent and -independent prostate cancer cells but not normal prostate epithelial cells. Downregulation of phosphorylated Akt and GSK-3b by deguelin promoted proteosomal degradation of b-catenin that resulted in decreased nuclear accumulation and inhibited transactivation of b-catenin-responsive genes. Deguelin-induced downregulation of proliferative (cyclin D1 and c-myc) and antiapoptotic proteins (Mcl-1, Bcl-xL and survivin) in prostate cancer cells culminated in the induction of apoptosis, inhibition of DNA synthesis and cell growth, altered membrane integrity, marked reduction of invasiveness, inhibition of anchorage-dependent and -independent colony formation. Our data demonstrated for the first time that deguelin inhibits the growth and survival of human androgen-independent prostate cancer cells, and its anticancer and antimetastatic activity occurs, at least in part through downregulating GSK-3b/b-catenin signaling pathway and antiapoptotic survival proteins. Taken together our study indicates that deguelin may have translational potential as therapeutic agent for advanced or metastatic prostate cancer.Prostate cancer is the most commonly diagnosed cancer in men, accounting for 30% of all malignant tumors. Men diagnosed with prostate cancer die, most often due to aggressive metastatic disease that fails to respond to hormonal therapy. While hormonal ablation usually works as a first line of treatment against localized tumors, after a few years most patients suffer a relapse when the malignancy becomes androgen independent, resulting in a highly metastatic cancer that is also resistant to both chemotherapy and irradiation.

Loss of PKCδ Induces Prostate Cancer Resistance to Paclitaxel through Activation of Wnt/β-Catenin Pathway and Mcl-1 Accumulation

“…These inhibitors used in combined therapy with paclitaxel resulted in an increased apoptotic response in comparison with single inhibitor or paclitaxel treatment, even in PKCd-silenced cells. Supporting our results, other authors showed that the inhibition of these pathways improved the apoptotic response to EGFR-targeting therapy in lung cancer (28), deguelin and microtubule-targeting drugs in prostate cancer (29,31), paclitaxel and irinotecan in colon cancer (30), or tamoxifen in glioma cells (24).…”

“…The abnormal activation of b-catenin in siRNA PKCd cells, as well as high Mcl-1 levels lead to diminished paclitaxel-induced apoptosis in prostate cancer cells. These results are supported by other studies that associate these changes with resistance to chemotherapeutic drugs (23,25,29,32).…”

“…On the basis of these articles, we propose that PKCd would modulate Mcl-1 by regulation of the Wnt/b-catenin pathway in prostate cancer cells. The Wnt/b-catenin pathway regulates embryogenesis, proliferation, cell differentiation, or migration, and it is abnormally activated in different tumor types (18,20,23,24,28,29). b-catenin is a strongly regulated factor with a central role in this pathway.…”

“…In the absence of Wnt activation, a degradation complex formed by GSK3b between other proteins is active and GSK3b phosphorylates b-catenin targeting it for proteasome degradation. Wnt activation implies the dissociation of the degradation complex and b-catenin translocation into the nucleus, where it activates the transcription of its target genes c-Myc and cyclin D1 which are involved in proliferation, migration, and survival (20,23,24,29,30). In prostate cancer cells, the knockdown of PKCd induced higher activation of b-catenin in comparison with siRNA control cells, as well as higher expression of its transcriptional targets.…”

“…The increased AurKA levels observed in the absence of PKCd were of particular interest given the link between the Wnt and Akt pathways (21,22). This pathway is also involved in resistance to microtubule targeting drugs (29,31) and, therefore, the activation of b-catenin was associated with the activation of Akt and consequent inactivation of GSK3b. This inactivation impaired the phosphorylation of Mcl-1 at Ser159 and phosphorylation of b-catenin, preventing their destruction, and favoring Mcl-1 accumulation and b-catenin activation.…”