Kumar Raj, Srinivasan Sowmyalakshmi, Koduru Srinivas, Pahari Pallab, Rohr Jürgen, Kyprianou Natasha, Damodaran Chendil
Department of Clinical Laboratory Sciences, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.
Cancer Prev Res (Phila). 2009 Mar;2(3):234-43. doi: 10.1158/1940-6207.CAPR-08-0129. Epub 2009 Feb 17.
The protein kinase Akt plays an important role in cell proliferation and survival in many cancers, including prostate cancer. Due to its kinase activity, it serves as a molecular conduit for inhibiting apoptosis and promoting angiogenesis in most cell types. In most of the prostate tumors, Akt signaling is constitutively activated due to the deletion or mutation of the tumor suppressor PTEN, which negatively regulates phosphatidylinositol 3-kinase through lipid phosphatase activity. Recently, we identified a natural compound, psoralidin, which inhibits Akt phosphorylation, and its consequent activation in androgen-independent prostate cancer (AIPC) cells. Furthermore, ectopic expression of Akt renders AIPC cells resistant to chemotherapy; however, psoralidin overcomes Akt-mediated resistance and induces apoptosis in AIPC cells. While dissecting the molecular events, both upstream and downstream of Akt, we found that psoralidin inhibits phosphatidylinositol 3-kinase activation and transcriptionally represses the activation of nuclear factor-kappaB and its target genes (Bcl-2, Survivin, and Bcl-xL, etc.), which results in the inhibition of cell viability and induction of apoptosis in PC-3 and DU-145 cells. Interestingly, psoralidin selectively targets cancer cells without causing any toxicity to normal prostate epithelial cells. In vivo xenograft assays substantiate these in vitro findings and show that psoralidin inhibits prostate tumor growth in nude mice. Our findings are of therapeutic significance in the management of prostate cancer patients with advanced or metastatic disease, as they provide new directions for the development of a phytochemical-based platform for prevention and treatment strategies for AIPC.
蛋白激酶Akt在包括前列腺癌在内的多种癌症的细胞增殖和存活中发挥着重要作用。由于其激酶活性，它在大多数细胞类型中充当抑制细胞凋亡和促进血管生成的分子通道。在大多数前列腺肿瘤中，由于肿瘤抑制因子PTEN的缺失或突变，Akt信号通路被持续激活，PTEN通过脂质磷酸酶活性对磷脂酰肌醇3激酶起负调节作用。最近，我们鉴定出一种天然化合物补骨脂素，它能抑制雄激素非依赖性前列腺癌（AIPC）细胞中Akt的磷酸化及其随后的激活。此外，Akt的异位表达使AIPC细胞对化疗产生抗性；然而，补骨脂素克服了Akt介导的抗性并诱导AIPC细胞凋亡。在剖析Akt上下游的分子事件时，我们发现补骨脂素抑制磷脂酰肌醇3激酶的激活，并转录抑制核因子-κB及其靶基因（Bcl-2、Survivin和Bcl-xL等）的激活，这导致PC-3和DU-145细胞的细胞活力受到抑制并诱导凋亡。有趣的是，补骨脂素选择性地靶向癌细胞，而对正常前列腺上皮细胞没有任何毒性。体内异种移植试验证实了这些体外研究结果，并表明补骨脂素可抑制裸鼠前列腺肿瘤的生长。我们的研究结果对晚期或转移性前列腺癌患者的治疗具有重要意义，因为它们为开发基于植物化学物质的AIPC预防和治疗策略平台提供了新的方向。
