Knockdown of Ki-67 by dicer-substrate small interfering RNA sensitizes bladder cancer cells to curcumin-induced tumor inhibition.
Knockdown of Ki-67 by dicer-substrate small interfering RNA sensitizes bladder cancer cells to curcumin-induced tumor inhibition.
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DOI：
10.1371/journal.pone.0048567
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ponnappa BC
中科院分区：
文献类型：
--
作者：
Pichu S;Krishnamoorthy S;Shishkov A;Zhang B;McCue P;Ponnappa BC
膀胱移行细胞癌（TCC）是泌尿道最常见的癌症。大多数TCC病例为浅表性，采用经尿道切除术（TUR）治疗。然而，复发率高，目前的治疗方法有诱导强全身毒性或引起疼痛性膀胱炎的缺点。因此，对膀胱癌的治疗发展新概念、寻找新药物具有重要的治疗价值。Ki-67是一种大核仁磷酸化蛋白，其表达与细胞增殖密切相关，姜黄素是一种从姜黄根茎中提取的植物化学物质，已被证明具有强大的抗癌特性。在这项研究中，我们评估了姜黄素和siRNA对大鼠（y -27）和人（T-24）膀胱癌细胞中Ki-67 mRNA （Ki-67-7）的联合作用。通过细胞活力测定、细胞凋亡和细胞周期分析来评价其抗癌作用。Ki-67-7 （10 nM）和姜黄素（10µM）单独处理时，效果中等。然而，在它们的联合存在下，膀胱癌细胞的增殖受到了深刻的抑制（约85%）；姜黄素与Ki-67-7联合作用的细胞凋亡率（36%）高于Ki-67-7单独作用的细胞凋亡率（14%）或姜黄素单独作用的细胞凋亡率（13%）。姜黄素和Ki-67-7在诱导细胞周期阻滞方面也有类似的协同作用。Western blot分析表明，Ki-67-7预处理通过不依赖于p53和p21的机制使膀胱癌细胞对姜黄素介导的凋亡和细胞周期阻滞敏感。这些数据表明，抗ki -67 siRNA和姜黄素的结合可能是一种有效的治疗膀胱癌细胞增殖的方法。
Transitional cell carcinoma (TCC) of the urinary bladder is the most common cancer of the urinary tract. Most of the TCC cases are of the superficial type and are treated with transurethral resection (TUR). However, the recurrence rate is high and the current treatments have the drawback of inducing strong systemic toxicity or cause painful cystitis. Therefore, it would be of therapeutic value to develop novel concepts and identify novel drugs for the treatment of bladder cancer. Ki-67 is a large nucleolar phosphoprotein whose expression is tightly linked to cell proliferation, and curcumin, a phytochemical derived from the rhizome Curcuma longa, has been shown to possess powerful anticancer properties. In this study, we evaluated the combined efficacy of curcumin and a siRNA against Ki-67 mRNA (Ki-67-7) in rat (AY-27) and human (T-24) bladder cancer cells. The anticancer effects were assessed by the determination of cell viability, apoptosis and cell cycle analysis. Ki-67-7 (10 nM) and curcumin (10 µM), when treated independently, were moderately effective. However, in their combined presence, proliferation of bladder cancer cells was profoundly (>85%) inhibited; the rate of apoptosis in the combined presence of curcumin and Ki-67-7 (36%) was greater than that due to Ki-67-7 (14%) or curcumin (13%) alone. A similar synergy between curcumin and Ki-67-7 in inducing cell cycle arrest was also observed. Western blot analysis suggested that pretreatment with Ki-67-7 sensitized bladder cancer cells to curcumin-mediated apoptosis and cell cycle arrest by p53- and p21-independent mechanisms. These data suggest that a combination of anti-Ki-67 siRNA and curcumin could be a viable treatment against the proliferation of bladder cancer cells.
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