Chiang Chun-Te, Way Tzong-Der, Lin Jen-Kun
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-ai Road, Taipei 10018, Taiwan.
Mol Cancer Ther. 2007 Jul;6(7):2127-38. doi: 10.1158/1535-7163.MCT-07-0107.
HER2 overexpression, which confers resistance to various therapeutic regimens, correlates with a poor clinical prognosis. In this study, we showed that luteolin, a naturally occurring flavonoid, is a potent stimulator of HER2 degradation. Luteolin effectively inhibited cell proliferation and induced apoptosis in HER2-overexpressing cancer cells. Furthermore, we found that low doses of luteolin up-regulated p21 expression and high doses of luteolin down-regulated its expression. Examination of the Akt/mammalian target of rapamycin (mTOR) signaling revealed that this signaling was only transiently inhibited by low doses of luteolin, which suggested that the inability to cause sustained Akt/mTOR inhibition may contribute to p21 induction and provide a survival advantage to HER2-overexpressing cancer cells. To test this hypothesis, we showed that the combined use of luteolin and mTOR inhibitor rapamycin prevented low doses of luteolin from inducing p21 expression, and HER2-overexpressing cancer cells would be sensitized toward luteolin-induced apoptosis. In addition, p21 small interfering RNA also increased the luteolin-induced cell death. In nude mice with xenografted SKOV3.ip1-induced tumors, luteolin significantly inhibited HER2 expression and tumor growth in a dose-dependent manner, and rapamycin further enhanced the effect of luteolin with a concomitant p21 inhibition. These results reveal an intriguing finding that suppressing p21 expression might have therapeutic implications and further suggest that combination of mTOR inhibitors may be a promising strategy to help increase the efficacy of preventive or therapeutic compounds against HER2-overexpressing tumors.
HER2过表达赋予对各种治疗方案的抗性，与不良的临床预后相关。在本研究中，我们表明木犀草素，一种天然存在的黄酮类化合物，是HER2降解的有效刺激剂。木犀草素有效抑制HER2过表达癌细胞的细胞增殖并诱导其凋亡。此外，我们发现低剂量木犀草素上调p21表达，高剂量木犀草素下调其表达。对Akt/雷帕霉素哺乳动物靶标（mTOR）信号传导的检测表明，该信号传导仅被低剂量木犀草素短暂抑制，这表明无法引起持续的Akt/mTOR抑制可能有助于p21诱导并为HER2过表达癌细胞提供生存优势。为了验证这一假设，我们表明木犀草素与mTOR抑制剂雷帕霉素联合使用可阻止低剂量木犀草素诱导p21表达，并且HER2过表达癌细胞对木犀草素诱导的凋亡会更敏感。此外，p21小干扰RNA也增加了木犀草素诱导的细胞死亡。在移植有SKOV3.ip1诱导肿瘤的裸鼠中，木犀草素以剂量依赖性方式显著抑制HER2表达和肿瘤生长，雷帕霉素进一步增强了木犀草素的作用并伴随p21抑制。这些结果揭示了一个有趣的发现，即抑制p21表达可能具有治疗意义，并进一步表明mTOR抑制剂的联合使用可能是一种有前景的策略，有助于提高针对HER2过表达肿瘤的预防或治疗化合物的疗效。
