Hypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells.
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.
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.
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Bourseau-Guilmain
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.
J A
JA
Menard
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.
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Lindqvist
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.
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Indira Chandran
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.
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Christianson
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.
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Cerezo Magaña
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.
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Lidfeldt
Center of Excellence in Biological and Medical Mass Spectrometry (CEBMMS), Lund University, 221 84 Lund, Sweden.|First Department of Surgery, Tokyo Medical University, Tokyo 160-0023, Japan.|Clinical Protein Science &Imaging, Biomedical Center, Biomedical Engineering, Lund University, 221 84 Lund, Sweden.
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Marko-Varga
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.|Center of Excellence in Biological and Medical Mass Spectrometry (CEBMMS), Lund University, 221 84 Lund, Sweden.
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Welinder
Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.|Department of Oncology and Radiotherapy, Skåne University Hospital, 221 85 Lund, Sweden.
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Belting
D000818:Animals; D000906:Antibodies / Q000737:chemistry / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000235:genetics* / Q000378:metabolism; D021941:Caveolae / Q000187:drug effects; D051242:Caveolin 1 / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002772:Cholera Toxin / Q000737:chemistry / Q000494:pharmacology; D034281:Dynamins / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D021381:Protein Transport / Q000187:drug effects; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D000906:Antibodies; D000951:Antigens, Neoplasm; C495540:CAV1 protein, human; D051242:Caveolin 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018796:Immunoconjugates; D020543:Proteome; D002772:Cholera Toxin; D034281:Dynamins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases