S-Space College of Medicine/School of Medicine (의과대학/대학원) Pharmacology (약리학전공) Journal Papers (저널논문_약리학전공)
HIF-1 is induced via EGFR activation and mediates resistance to anoikis-like cell death under lipid rafts/caveolae-disrupting stress
- Lee, Seong-Hee; Koo, Kyung Hee; Park, Jong-Wan; Kim, Hee-Jung; Park, Jong Bae; Kim, Yong-Nyun; Park, Byung-Kiu; Ye, Sang-Kyu
- Issue Date
- OXFORD UNIV PRESS
- CARCINOGENESIS; Vol.30 12; 1997-2004
- 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.
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