HIF-1 is induced via EGFR activation and mediates resistance to anoikis-like cell death under lipid rafts/caveolae-disrupting stress

Abstract

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-1alpha plays a role in this process, we here explored a possible connection between lipid rafts and HIF-1alpha. We investigated whether HIF-1alpha is regulated during cholesterol depletion/rafts disruption in A431 cells in normoxic conditions. Methyl-beta cyclodextrin (MbetaCD), which induces cholesterol depletion, upregulated HIF-1alpha 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. MbetaCD treatment induced HIF-1alpha upregulation at both the transcriptional and translational levels but not at the posttranslational levels. In addition, MbetaCD robustly induced vascular endothelial growth factor production and stimulated an hypoxia response element-driven luciferase reporter activity under normoxic conditions, indicating that MbetaCD-induced HIF-1alpha is functionally activated. Both EGFR activity and HIF-1alpha expression were higher in the attached cells than in the detached cells after MbetaCD treatment. Furthermore, inhibition of HIF-1alpha by RNA interference accelerated cell detachment, thus increasing cell death, indicating that HIF-1alpha expression attenuates MbetaCD-induced anoikis-like cell death. These data suggest that, depending on cholesterol levels, lipid rafts or membrane fluidity are probably to regulate HIF-1alpha expression in normoxia by modulating rafts protein activities such as EGFR, and this connection between lipid rafts and HIF-1alpha regulation may provide cell survival under membrane-disturbing stress.

Preclinical Development of a Nontoxic Oral Formulation of Monoethanolamine, a Lipid Precursor, for Prostate Cancer Treatment

“…(44). Although lipid-mediated regulation of HIF1-α represents an untapped research area, there exists one report which suggests that changes in membrane properties can modulate HIF1-α expression by affecting EGFR function (45). This raises the possibility that accumulation of lipids may hamper the function of membrane proteins that are positive regulators of HIF1-α expression.…”

Influence of stress on extracellular matrix and integrin biology

“…The impact of hypoxia on integrin biology could explain why it could protect cells against anoıkis (Rohwer et al, 2008;Lee et al, 2009) and contribute to cancer invasion and metastasis (Sullivan and Graham, 2007).…”

Lipid Rafts and Fas/CD95 Signaling in Cancer Chemotherapy

“…Data from prostate cancer animal models have shown that raising or lowering cholesterol, a critical component of rafts [81,82], led to tumor growth promotion or inhibition, respectively [83,84]. Lipid raft cholesterol regulates apoptotic cell death in prostate cancer cells, through epidermal growth factor receptor (EGFR)-mediated Akt and extracellular signal-regulated kinase (ERK) pathways [85].…”