HIF-1 is induced via EGFR activation and mediates resistance to anoikis-like cell death under lipid rafts/caveolae-disrupting stress
HIF-1 is induced via EGFR activation and mediates resistance to anoikis-like cell death under lipid rafts/caveolae-disrupting stress
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DOI：
10.1093/carcin/bgp233
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发表时间：
2009-12-01
期刊：
影响因子：
4.7
通讯作者：
Kim, Yong-Nyun
中科院分区：
文献类型：
--
作者：
Lee, Seong-Hee;Koo, Kyung Hee;Kim, Yong-Nyun
质膜微区，即脂筏，参与细胞功能的调节，如细胞存活和黏附。就其完整性和功能而言，胆固醇是脂筏的关键成分，而脂筏因胆固醇耗尽而破坏，可导致细胞脱离诱导死亡。低氧诱导因子-1(HIF-1)α在低氧中稳定，并反式激活许多细胞适应低氧所需的基因。它也是由非缺氧性刺激诱导的，有助于细胞存活。因为低氧抑制胆固醇合成，而HIF-1α在这一过程中起作用，我们在这里探索了脂筏和HIF-1α之间的可能联系。我们研究了在常氧条件下，HIF-1α是否在A431细胞的胆固醇耗竭/筏子破坏过程中受到调控。甲基-β-环糊精(M-βCD)诱导胆固醇耗竭，即使在常氧条件下也上调HIF-1α，这种上调需要表皮生长因子受体(EGFR)和细胞外信号调节激酶1和2的激活，而不是Akt的激活。MβCD诱导HIF-1α在转录和翻译水平上表达上调，但不在翻译后水平上表达。此外，在常氧条件下，M-β-CD强烈诱导血管内皮生长因子的产生，并刺激低氧反应元件驱动的荧光素酶报告活性，表明M-β-CD诱导的HIF-1α被功能性激活。经M-β-CD处理后，贴壁细胞的EGFR活性和HIF-1α表达均高于贴壁细胞。此外，RNA干扰抑制HIF-1α可加速细胞脱离，从而增加细胞死亡，表明HIF-1α的表达减弱了MβCD诱导的类失巢细胞死亡。这些数据表明，根据胆固醇水平的不同，脂筏或膜流动性可能通过调节脂筏蛋白的活性(如EGFR)来调节常氧下HIF-1α的表达，这种脂筏与HIF-1α调控之间的联系可能提供了细胞在膜干扰应激下的存活。
The plasma membrane microdomains, lipid rafts, are involved in regulation of cellular functions such as cell survival and adhesion. Cholesterol is a critical component of lipid rafts in terms of their integrity and functions and rafts disruption by cholesterol depletion can induce detachment-induced cell death. Hypoxia inducible factor-1 (HIF-1) alpha is stabilized in hypoxia and transactivates numerous genes required for cellular adaptation to hypoxia. It is also induced by non-hypoxic stimuli and contributes to cell survival. Because hypoxia inhibits cholesterol synthesis and HIF-1 alpha plays a role in this process, we here explored a possible connection between lipid rafts and HIF-1 alpha. We investigated whether HIF-1 alpha is regulated during cholesterol depletion/rafts disruption in A431 cells in normoxic conditions. Methyl-beta cyclodextrin (M beta CD), which induces cholesterol depletion, upregulated HIF-1 alpha even under normoxic conditions and this upregulation required epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase 1 and 2 activation, but not Akt activation. M beta CD treatment induced HIF-1 alpha upregulation at both the transcriptional and translational levels but not at the posttranslational levels. In addition, M beta CD robustly induced vascular endothelial growth factor production and stimulated an hypoxia response element-driven luciferase reporter activity under normoxic conditions, indicating that M beta CD-induced HIF-1 alpha is functionally activated. Both EGFR activity and HIF-1 alpha expression were higher in the attached cells than in the detached cells after M beta CD treatment. Furthermore, inhibition of HIF-1 alpha by RNA interference accelerated cell detachment, thus increasing cell death, indicating that HIF-1 alpha expression attenuates M beta CD-induced anoikis-like cell death. These data suggest that, depending on cholesterol levels, lipid rafts or membrane fluidity are probably to regulate HIF-1 alpha expression in normoxia by modulating rafts protein activities such as EGFR, and this connection between lipid rafts and HIF-1 alpha regulation may provide cell survival under membrane-disturbing stress.