Overexpression of CD44 standard isoform upregulates HIF-1alpha signaling in hypoxic breast cancer cells

[Speaker] Dayoung Ryu:1
[Co-author] In-Geun Ryoo:1, Mi-Kyoung Kawk:1
1:College of Pharmacy, The Catholic University of Korea, Korea

CD44, a cell surface adhesion receptor for hyaluronic acid (HA), is often highly expressed in various cancers and is involved in cancer cell proliferation and migration. It has been reported that hypoxia elevated CD44 expression in tumor cells via hypoxia-inducible factor-1alpha (HIF-1alpha), which resulted in facilitated cancer proliferation and migration. In the current study, we investigated the role of CD44 in HIF-1alpha regulation by establishing the stable breast cancer MCF7 cell line (pCD44s-MCF7) that overexpresses CD44 standard form. First, cell proliferation rate was higher in pCD44s-MCF7 than that in the control MCF7 under normoxic condition. Second, the levels of hypoxia-inducible HIF-1alpha and vascular endothelial growth factor were significantly high in pCD44s-MCF7 compared to the control MCF7. In addition, the level of hypoxia-inducible HIF-1alpha was further increased following HA incubation in pCD44s-MCF7, which confirmed the CD44-dependent HIF-1alpha activation. Third, as a molecular event of CD44-mediated HIF-1alpha signaling enhancement, the extracellular signal-regulated kinase (ERK) pathway was speculated. The level of phosphorylated ERK was high in the hypoxic pCD44s-MCF7 compared with the hypoxic MCF7, and HIF-1alpha accumulation was largely inhibited pharmacological inhibitors of ERK. Fourth, metabolic change favoring glycolytic pathway is one of mechanisms of HIF-1alpha-mediated cancer cell survival. The hypoxia-inducible expression levels of glycolysis-related proteins pyruvate dehydrogenase kinase-1 (PDK1), Hexokinase-2 (HK2) and glucose transporter-1 (GLUT1) were greater in pCD44-MCF7 than in the control MCF7. As a consequence of facilitated HIF-1alpha-mediated adaptation, pCD44-MCF7 cells showed a higher viability under hypoxia and displayed enhanced hypoxia-induced cell motility in wound healing assay. Taken together, these results suggested that the CD44 standard isoform activated HIF-1alpha-signaling to enhance cell viability and motility through the ERK pathway.
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