Prostate Diseases Prevention and Treatment Research Center and Department of Pathophysiology, Norman Bethune College of Medicine, Jilin University, Xinmin Street, Changchun, 130021, PR China.
BMC Cancer. 2010 Aug 10;10:418. doi: 10.1186/1471-2407-10-418.
Prostate cancer is a leading cause of cancer-related death in men worldwide. Survivin is a member of the inhibitor of apoptosis (IAP) protein family that is expressed in the majority of human tumors including prostate cancer, but is barely detectable in terminally differentiated normal cells. Downregulation of survivin could sensitize prostate cancer cells to chemotherapeutic agents in vitro and in vivo. Selenium is an essential trace element. Several studies have shown that selenium compounds inhibit the growth of prostate cancer cells. The objective of this study is to investigate whether survivin gene silencing in conjunction with selenium treatment could enhance the therapeutic efficacy for prostate cancer and to elucidate the underlying mechanisms.
Expression of survivin was analyzed in a collection of normal and malignant prostatic tissues by immunohistochemical staining. In vitro studies were conducted in PC-3M, C4-2B, and 22Rv1 prostate cancer cells. The effect of selenium on survivin expression was analyzed by Western blotting and semi-quantitative RT-PCR. Survivin gene knockdown was carried out by transfecting cells with a short hairpin RNA (shRNA) designed against survivin. Cell proliferation was quantitated by the 3-(4,5-Dimethylthiazol-2-yl)- 2,5-Diphenyltetrazolium Bromide (MTT) assay and apoptosis by propidium iodide staining followed by flow cytometry analysis. Finally, in vivo tumor growth assay was performed by establishing PC-3M xenograft in nude mice and monitoring tumor growth following transfection and treatment.
We found that survivin was undetectable in normal prostatic tissues but was highly expressed in prostate cancers. Survivin knockdown or selenium treatment inhibited the growth of prostate cancer cells, but the selenium effect was modest. In contrast to what have been observed in other cell lines, selenium treatment had little or no effect on survivin expression in several androgen-independent prostate cancer cell lines. Survivin knockdown sensitized these cells to selenium growth inhibition and apoptosis induction. In nude mice bearing PC-3M xenografts, survivin knockdown synergizes with selenium in inhibiting tumor growth.
Selenium could inhibit the growth of hormone-refractory prostate cancer cells both in vitro and in vivo, but the effects were modest. The growth inhibition was not mediated by downregulating survivin expression. Survivin silencing greatly enhanced the growth inhibitory effects of selenium.
前列腺癌是全世界男性癌症相关死亡的主要原因。Survivin 是凋亡抑制蛋白 (IAP) 家族的成员，在包括前列腺癌在内的大多数人类肿瘤中表达，但在终末分化的正常细胞中几乎检测不到。Survivin 的下调可使前列腺癌细胞对体外和体内化疗药物敏感。硒是一种必需的微量元素。多项研究表明，硒化合物可抑制前列腺癌细胞的生长。本研究的目的是探讨 Survivin 基因沉默联合硒处理是否能增强前列腺癌的治疗效果，并阐明其潜在机制。
通过免疫组织化学染色分析正常和恶性前列腺组织中 Survivin 的表达。在 PC-3M、C4-2B 和 22Rv1 前列腺癌细胞中进行体外研究。通过 Western blot 和半定量 RT-PCR 分析硒对 Survivin 表达的影响。通过转染针对 Survivin 的短发夹 RNA (shRNA) 来进行 Survivin 基因敲低。通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴盐 (MTT) 测定法定量细胞增殖，通过碘化丙啶染色后流式细胞术分析测定细胞凋亡。最后，通过建立 PC-3M 异种移植瘤在裸鼠中进行体内肿瘤生长试验，并在转染和治疗后监测肿瘤生长。
我们发现 Survivin 在正常前列腺组织中无法检测到，但在前列腺癌中高度表达。Survivin 敲低或硒处理抑制前列腺癌细胞生长，但硒的作用较小。与在其他细胞系中观察到的情况相反，硒处理对几种雄激素非依赖性前列腺癌细胞系中的 Survivin 表达几乎没有影响或没有影响。Survivin 敲低使这些细胞对硒的生长抑制和凋亡诱导敏感。在携带 PC-3M 异种移植瘤的裸鼠中，Survivin 敲低与硒协同抑制肿瘤生长。
硒在体外和体内均可抑制激素难治性前列腺癌细胞的生长，但作用较小。生长抑制不是通过下调 Survivin 表达介导的。Survivin 沉默大大增强了硒的生长抑制作用。
