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

Bourseau-Guilmain E, Menard JA, Lindqvist E, Indira Chandran V, Christianson HC, Cerezo MagaƱa M, Lidfeldt J, Marko-Varga G, Welinder C, Belting M

Nat Commun 7 (-) 11371 [2016-04-20; online 2016-04-20]

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.

Targeted and Structural Proteomics [Service]

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PubMed 27094744

DOI 10.1038/ncomms11371

Crossref 10.1038/ncomms11371

ncomms11371

pmc PMC4842985