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Fenofibrate inhibits hypoxia-inducible factor-1 alpha and carbonic anhydrase expression through activation of AMP-activated protein kinase/HO-1/Sirt1 pathway in glioblastoma cells
Environmental Toxicology ( IF 4.5 ) Pub Date : 2021-09-14 , DOI: 10.1002/tox.23369
Chingju Lin, Sheng-Wei Lai, Ching-Kai Shen, Chao-Wei Chen, Cheng-Fang Tsai, Yu-Shu Liu, Dah-Yuu Lu, Bor-Ren Huang

Cancer and its associated conditions have significant impacts on public health at many levels worldwide, and cancer is the leading cause of death among adults. Peroxisome proliferator-activated receptor α (PPARα)-specific agonists, fibrates, have been approved by the Food and Drug Administration for managing hyperlipidemia. PPARα-specific agonists exert anti-cancer effects in many human cancer types, including glioblastoma (GBM). Recently, we have reported that the hypoxic state in GBM stabilizes hypoxia-inducible factor-1 alpha (HIF-1α), thus contributing to tumor escape from immune surveillance by activating the expression of the pH-regulating protein carbonic anhydrase IX (CA9). In this study, we aimed to study the regulatory effects of the PPARα agonist fibrate on the regulation of HIF-1α expression and its downstream target protein in GBM. Our findings showed that fenofibrate is the high potency compound among the various fibrates that inhibit hypoxia-induced HIF-1α and CA9 expression in GBM. Moreover, fenofibrate-inhibited HIF-1α expression is mediated by HO-1 activation in GBM cells through the AMP-activated protein kinase (AMPK) pathway. In addition, fenofibrate-enhanced HO-1 upregulation activates SIRT1 and leads to subsequent accumulation of SIRT1 in the nucleus, which further promotes HIF-1α deacetylation and inhibits CA9 expression. Using a protein synthesis inhibitor, cycloheximide, we also observed that fenofibrate inhibited HIF-1α protein synthesis. In addition, the administration of the proteasome inhibitor MG132 showed that fenofibrate promoted HIF-1α protein degradation in GBM. Hence, our results indicate that fenofibrate is a useful anti-GBM agent that modulates hypoxia-induced HIF-1α expression through multiple cellular pathways.

中文翻译:

非诺贝特通过激活胶质母细胞瘤细胞中的 AMP 活化蛋白激酶/HO-1/Sirt1 通路抑制缺氧诱导因子 1 α 和碳酸酐酶的表达

癌症及其相关疾病对全世界许多层面的公共卫生产生重大影响,而癌症是成年人死亡的主要原因。过氧化物酶体增殖物激活受体 α (PPARα) 特异性激动剂贝特类已被美国食品和药物管理局批准用于管理高脂血症。PPARα 特异性激动剂在许多人类癌症类型中发挥抗癌作用,包括胶质母细胞瘤 (GBM)。最近,我们报道了 GBM 中的缺氧状态稳定了缺氧诱导因子 1 α (HIF-1α),从而通过激活 pH 调节蛋白碳酸酐酶 IX (CA9) 的表达来促进肿瘤逃避免疫监视。在本研究中,我们旨在研究 PPARα 激动剂贝特对 GBM 中 HIF-1α 表达及其下游靶蛋白的调节作用。我们的研究结果表明,非诺贝特是各种贝特类中的高效化合物,可抑制 GBM 中缺氧诱导的 HIF-1α 和 CA9 表达。此外,非诺贝特抑制的 HIF-1α 表达是通过 AMP 活化蛋白激酶 (AMPK) 途径由 GBM 细胞中的 HO-1 激活介导的。此外,非诺贝特增强的 HO-1 上调激活 SIRT1 并导致 SIRT1 随后在细胞核中积累,这进一步促进 HIF-1α 脱乙酰化并抑制 CA9 表达。使用蛋白质合成抑制剂放线菌酮,我们还观察到非诺贝特抑制 HIF-1α 蛋白质合成。此外,蛋白酶体抑制剂 MG132 的给药表明,非诺贝特促进了 GBM 中 HIF-1α 蛋白的降解。因此,
更新日期:2021-11-03
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