Ataie-Kachoie Parvin, Pourgholami Mohammad H, Bahrami-B Farnaz, Badar Samina, Morris David L
Department of Surgery, St George Hospital Sydney, Australia.
University of New South Wales Department of Surgery, St George and Sutherland Clinical School Sydney, Australia.
Am J Cancer Res. 2015 Jan 15;5(2):575-88. eCollection 2015.
Hypoxia-inducible factor (HIF)-1α is the key cellular survival protein under hypoxia, and is associated with tumor progression and angiogenesis. We have recently shown the inhibitory effects of minocycline on ovarian tumor growth correlated with attenuation of vascular endothelial growth factor (VEGF) and herein report a companion laboratory study to test if these effects were the result of HIF-1α inhibition. In vitro, human ovarian carcinoma cell lines (A2780, OVCAR-3 and SKOV-3) were utilized to examine the effect of minocycline on HIF-1 and its upstream pathway components to elucidate the underlying mechanism of action of minocycline. Mice harboring OVCAR-3 xenografts were treated with minocycline to assess the in vivo efficacy of minocycline in the context of HIF-1. Minocycline negatively regulated HIF-1α protein levels in a concentration-dependent manner and induced its degradation by a mechanism that is independent of prolyl-hydroxylation. The inhibition of HIF-1α was found to be associated with up-regulation of endogenous p53, a tumor suppressor with confirmed role in HIF-1α degradation. Further studies demonstrated that the effect of minocycline was not restricted to proteasomal degradation and that it also caused down-regulation of HIF-1α translation by suppressing the AKT/mTOR/p70S6K/4E-BP1 signaling pathway. Minocycline treatment of mice bearing established ovarian tumors, led to suppression of HIF-1α accompanied by up-regulation of p53 protein levels and inactivation of AKT/mTOR/p70S6K/4E-BP1 pathway. These data reveal the therapeutic potential of minocycline in ovarian cancer as an agent that targets the pro-oncogenic factor HIF-1α through multiple mechanisms.
缺氧诱导因子（HIF）-1α是细胞在缺氧状态下关键的生存蛋白，与肿瘤进展和血管生成相关。我们最近发现米诺环素对卵巢肿瘤生长具有抑制作用，这与血管内皮生长因子（VEGF）的减弱相关，在此报告一项配套的实验室研究，以检验这些作用是否是HIF-1α抑制的结果。在体外，利用人卵巢癌细胞系（A2780、OVCAR-3和SKOV-3）来研究米诺环素对HIF-1及其上游通路成分的影响，以阐明米诺环素潜在的作用机制。用米诺环素处理携带OVCAR-3异种移植瘤的小鼠，以评估米诺环素在HIF-1背景下的体内疗效。米诺环素以浓度依赖性方式负向调节HIF-1α蛋白水平，并通过一种不依赖脯氨酰羟化的机制诱导其降解。发现HIF-1α的抑制与内源性p53的上调相关，p53是一种在HIF-1α降解中具有确定作用的肿瘤抑制因子。进一步研究表明，米诺环素的作用不仅限于蛋白酶体降解，它还通过抑制AKT/mTOR/p70S6K/4E-BP1信号通路导致HIF-1α翻译下调。米诺环素治疗已建立卵巢肿瘤的小鼠，导致HIF-1α受到抑制，同时伴有p53蛋白水平上调以及AKT/mTOR/p70S6K/4E-BP1通路失活。这些数据揭示了米诺环素在卵巢癌治疗中的潜力，它作为一种通过多种机制靶向促癌因子HIF-1α的药物。
