Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, USA.
Int J Cancer. 2011 Dec 15;129(12):2916-27. doi: 10.1002/ijc.25949. Epub 2011 Apr 7.
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-3β by deguelin promoted proteosomal degradation of β-catenin that resulted in decreased nuclear accumulation and inhibited transactivation of β-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-3β/β-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.
生存途径的激活与化学抗性和雄激素非依赖性的进展有关，这给转移性前列腺癌的成功治疗带来了重大障碍。从 Mundulea sericea 中分离出的 Rotenoid deguelin 对几种类型的癌症具有抗癌作用；然而，其对前列腺癌的抗肿瘤作用机制尚不清楚。我们的研究目的是阐明 deguelin 对前列腺癌细胞生长的影响及其潜在的作用机制。Deguelin 降低了雄激素依赖性和非依赖性前列腺癌细胞的活力，但对正常前列腺上皮细胞没有影响。Deguelin 下调磷酸化 Akt 和 GSK-3β，促进 β-连环蛋白的蛋白酶体降解，导致核内积累减少，并抑制β-连环蛋白反应基因的转录激活。Deguelin 诱导前列腺癌细胞中增殖（cyclin D1 和 c-myc）和抗凋亡蛋白（Mcl-1、Bcl-xL 和 survivin）的下调，最终导致细胞凋亡、DNA 合成和细胞生长抑制、膜完整性改变、侵袭性显著降低、锚定依赖性和非依赖性集落形成抑制。我们的数据首次表明，Deguelin 抑制人雄激素非依赖性前列腺癌细胞的生长和存活，其抗癌和抗转移活性至少部分是通过下调 GSK-3β/β-连环蛋白信号通路和抗凋亡生存蛋白来实现的。总之，我们的研究表明，Deguelin 可能作为晚期或转移性前列腺癌的治疗剂具有转化潜力。
