Bortezomib represses HIF-1α protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells
Bortezomib represses HIF-1α protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells
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DOI：
10.1007/s00109-011-0805-8
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发表时间：
2012-01-01
影响因子：
4.7
通讯作者：
Liakos, Panagiotis
中科院分区：
文献类型：
--
作者：
Befani, Christina D.;Vlachostergios, Panagiotis J.;Liakos, Panagiotis
硼替佐米是第一种在临床环境中显示出抗肿瘤活性的蛋白酶体抑制剂（PI），尤其用于治疗血液系统恶性肿瘤。在临床前水平，其作用表现为在许多肿瘤类型中诱导生长停滞和细胞凋亡，包括雄激素依赖性（AD）和雄激素非依赖性（AI）前列腺癌细胞。缺氧诱导因子 -1α（HIF -1α）直接参与肿瘤生长，是抗癌治疗中研究最多且最有前景的分子靶点之一，在前列腺癌中经常过度表达。据报道，硼替佐米也通过抑制HIF -1α来抑制肿瘤生长。在本研究中，我们研究了硼替佐米对LNCaP（AD）和PC3（AI）前列腺癌细胞中HIF -1α的表达、活性和定位的影响。首先，我们表明HIF -1α蛋白水平和活性的缺氧上调涉及PI3K/Akt/mTOR和p44/42 MAPK途径。其次，硼替佐米在常氧和缺氧条件下均抑制HIF -1α蛋白的表达，抑制HIF -1转录活性并减弱血管内皮生长因子的释放。这些作用与硼替佐米导致磷酸化Akt、磷酸化p70S6K和磷酸化S6RP去磷酸化的能力相关，从而使已知在翻译水平上HIF -1α蛋白表达所必需的途径失活。此外，硼替佐米还消除p44/42 MAPK磷酸化，这导致HIF -1α的核转位减少。综上所述，这些结果表明，在AD和AI前列腺癌细胞中，硼替佐米分别通过抑制PI3K/Akt/mTOR和MAPK途径来抑制HIF -1α蛋白合成及其核靶向。
Bortezomib represents the first proteasome inhibitor (PI) with demonstrated antitumor activity in the clinical setting, particularly for treatment of hematological malignancies. At the preclinical level, its action is shown to be mediated by induction of growth arrest and apoptosis in many tumor types, including androgen-dependent (AD) and androgen-independent (AI) prostate cancer (PCa) cells. Hypoxiainducible factor-1 alpha (HIF-1 alpha), which is directly involved in tumor growth, is one of the most studied and promising molecular targets for anti-cancer therapy and is often overexpressed in PCa. Bortezomib has been reported to impair tumor growth by also inhibiting HIF-1 alpha. In this study, we investigated the effect of bortezomib on the expression, activity and localization of HIF-1 alpha in LNCaP (AD) and PC3 (AI) PCa cells. First, we show that hypoxic upregulation of HIF-1 alpha protein levels and activity involves both the PI3K/Akt/mTOR and p44/42 MAPK pathways. Second, bortezomib inhibits expression of HIF-1 alpha protein under both normoxic and hypoxic conditions, represses HIF-1 transcriptional activity and attenuates the release of vascular endothelial growth factor. These effects correlate with the ability of bortezomib to cause dephosphorylation of phospho-Akt, phospho-p70S6K, and phospho-S6RP, thus inactivating a pathway known to be required for HIF-1 alpha protein expression at the translational level. Furthermore, bortezomib also abrogates p44/42 MAPK phosphorylation, which results to reduced nuclear translocation of HIF-1 alpha. Taken together, these results suggest that bortezomib inhibits HIF-1 alpha protein synthesis and its nuclear targeting through suppression of PI3K/Akt/mTOR and MAPK pathways, respectively, in both AD and AI PCa cells.