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Hypoxia-Induced Caveolin-1 Expression Promotes Migration and Invasion of Tumor Cells
J Castillo Bennett1,2,3, P Silva3,4, S Martinez1,2
1Center for Studies on Exercise, Metabolism and Cancer (CEMC), Advanced Center for Chronic Diseases (ACCDiS), Faculty of Medicine, Universidad de Chile, Santiago, Chile.
Current Molecular Medicine
|September 28, 2018
Summary
Hypoxia promotes cancer cell migration and invasion by increasing Caveolin-1 (CAV1) expression, which is dependent on hypoxia-inducible factor 1-alpha (HIF1α) and src family kinase activation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Tumor hypoxia is linked to poor prognosis due to enhanced cancer cell migration, invasion, and metastasis.
- Hypoxia-induces hypoxia-inducible factors (HIFs), primarily HIF1α, and upregulates target genes like Caveolin-1 (CAV1).
- CAV1 expression, particularly phosphorylated CAV1, promotes cancer cell migration, invasion, and metastasis.
Purpose of the Study:
- To investigate if hypoxia-induced CAV1 expression is essential for hypoxia-driven cancer cell migration and invasion.
- To elucidate the role of HIF1α and src family kinases in hypoxia-mediated CAV1 induction and subsequent cancer cell motility.
Main Methods:
- Exposure of B16-F10 murine melanoma and HT29(US) colon adenocarcinoma cells to hypoxic conditions (1% O2).
- Assessment of CAV1 and HIF1α protein levels via western blotting.
- Knock-down of endogenous CAV1 and HIF1α using shRNA constructs.
- Evaluation of cell migration and invasion using Boyden Chamber and Matrigel assays, respectively.
- Pharmacological inhibition of HIF and src-family kinases (PP2).
Main Results:
- Hypoxia significantly increased CAV1 protein levels in both cell lines in a HIF1α-dependent manner.
- Knock-down of CAV1 abolished hypoxia-induced migration in both B16-F10 and HT29(US) cells.
- Pharmacological inhibition of HIF and src-family kinases (PP2) blocked hypoxia-induced migration and invasion.
- Hypoxia-induced migration was dependent on CAV1 phosphorylation by src-family kinases.
Conclusions:
- Hypoxia-induced migration and invasion in metastatic cancer cells are critically dependent on HIF1α-mediated induction of CAV1 expression.
- Activation of src family kinases and subsequent CAV1 phosphorylation are key events in hypoxia-driven cancer cell motility.
- Targeting the HIF1α-CAV1 signaling axis presents a potential therapeutic strategy for inhibiting metastasis in hypoxic tumors.
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