Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41110 Larissa, Greece.
J Mol Med (Berl). 2012 Jan;90(1):45-54. doi: 10.1007/s00109-011-0805-8. Epub 2011 Sep 10.
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. Hypoxia-inducible factor-1α (HIF-1α), 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-1α. In this study, we investigated the effect of bortezomib on the expression, activity and localization of HIF-1α in LNCaP (AD) and PC3 (AI) PCa cells. First, we show that hypoxic upregulation of HIF-1α protein levels and activity involves both the PI3K/Akt/mTOR and p44/42 MAPK pathways. Second, bortezomib inhibits expression of HIF-1α 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-1α protein expression at the translational level. Furthermore, bortezomib also abrogates p44/42 MAPK phosphorylation, which results to reduced nuclear translocation of HIF-1α. Taken together, these results suggest that bortezomib inhibits HIF-1α protein synthesis and its nuclear targeting through suppression of PI3K/Akt/mTOR and MAPK pathways, respectively, in both AD and AI PCa cells.
硼替佐米是首个在临床环境中具有抗肿瘤活性的蛋白酶体抑制剂 (PI)，尤其适用于治疗血液系统恶性肿瘤。在临床前水平，其作用被证明是通过诱导许多肿瘤类型（包括雄激素依赖性 (AD) 和雄激素非依赖性 (AI) 前列腺癌 (PCa) 细胞的生长停滞和凋亡来介导的。缺氧诱导因子-1α (HIF-1α) 直接参与肿瘤生长，是最受研究和有前途的抗癌治疗分子靶点之一，在 PCa 中常过度表达。硼替佐米已被报道通过抑制 HIF-1α 来抑制肿瘤生长。在这项研究中，我们研究了硼替佐米对 LNCaP (AD) 和 PC3 (AI) PCa 细胞中 HIF-1α 的表达、活性和定位的影响。首先，我们表明，缺氧上调 HIF-1α 蛋白水平和活性涉及 PI3K/Akt/mTOR 和 p44/42 MAPK 途径。其次，硼替佐米在常氧和低氧条件下均抑制 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使磷酸化 Akt、磷酸化 p70S6K 和磷酸化 S6RP 去磷酸化的能力相关，从而使翻译水平上 HIF-1α 蛋白表达所需的途径失活。此外，硼替佐米还阻断 p44/42 MAPK 磷酸化，导致 HIF-1α 核转位减少。综上所述，这些结果表明，硼替佐米通过抑制 PI3K/Akt/mTOR 和 MAPK 途径分别抑制 AD 和 AI PCa 细胞中 HIF-1α 蛋白的合成及其核靶向。
