Hypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells

E. Bourseau-Guilmain, J. A. Menard, E. Lindqvist, V. Indira Chandran, H. C. Christianson, M. Cerezo Magaña, J. Lidfeldt, G. Marko-Varga, C. Welinder and M. Belting ()
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E. Bourseau-Guilmain: Section of Oncology and Pathology, Lund University
J. A. Menard: Section of Oncology and Pathology, Lund University
E. Lindqvist: Section of Oncology and Pathology, Lund University
V. Indira Chandran: Section of Oncology and Pathology, Lund University
H. C. Christianson: Section of Oncology and Pathology, Lund University
M. Cerezo Magaña: Section of Oncology and Pathology, Lund University
J. Lidfeldt: Section of Oncology and Pathology, Lund University
G. Marko-Varga: Center of Excellence in Biological and Medical Mass Spectrometry (CEBMMS), Lund University
C. Welinder: Section of Oncology and Pathology, Lund University
M. Belting: Section of Oncology and Pathology, Lund University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. The identification of cancer cell internalizing antigens for drug targeting to the hypoxic tumour niche remains a challenge of high clinical relevance. Here we show that hypoxia down-regulates the surface proteome at the global level and, more specifically, membrane proteome internalization. We find that hypoxic down-regulation of constitutive endocytosis is HIF-independent, and involves caveolin-1-mediated inhibition of dynamin-dependent, membrane raft endocytosis. Caveolin-1 overexpression inhibits protein internalization, suggesting a general negative regulatory role of caveolin-1 in endocytosis. In contrast to this global inhibitory effect, we identify several proteins that can override caveolin-1 negative regulation, exhibiting increased internalization at hypoxia. We demonstrate antibody-mediated cytotoxin delivery and killing specifically of hypoxic cells through one of these proteins, carbonic anhydrase IX. Our data reveal that caveolin-1 modulates cell-surface proteome turnover at hypoxia with potential implications for specific targeting of the hypoxic tumour microenvironment.

Date: 2016
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DOI: 10.1038/ncomms11371

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