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

E Bourseau-Guilmain1, J A Menard1, E Lindqvist1

  • 1Department of Clinical Sciences, Section of Oncology and Pathology, Lund University, 221 85 Lund, Sweden.

Nature Communications
|April 21, 2016
PubMed

Insights

Hypoxia reduces cancer cell surface protein uptake, but carbonic anhydrase IX can be targeted for drug delivery to kill hypoxic tumor cells.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Hypoxia (low oxygen) increases tumor aggressiveness and treatment resistance.
  • Targeting antigens on cancer cells within hypoxic tumor niches is clinically important but challenging.

Purpose of the Study:

  • To investigate how hypoxia affects the cell surface proteome and membrane protein internalization.
  • To identify specific antigens for targeted drug delivery to hypoxic tumor cells.

Main Methods:

  • Global proteomic analysis of hypoxic cancer cells.
  • Investigated hypoxia-inducible factor (HIF)-independent endocytosis pathways.
  • Utilized caveolin-1 overexpression and inhibition studies.
  • Demonstrated antibody-mediated cytotoxin delivery targeting carbonic anhydrase IX.

Main Results:

  • Hypoxia globally down-regulates surface proteome and membrane protein internalization.
  • Caveolin-1 inhibits dynamin-dependent, membrane raft endocytosis in a HIF-independent manner.
  • Carbonic anhydrase IX (CAIX) internalizes more in hypoxic cells, overriding caveolin-1 inhibition.
  • Antibody-drug conjugates targeting CAIX selectively kill hypoxic cancer cells.

Conclusions:

  • Caveolin-1 negatively regulates endocytosis, impacting cell surface proteome turnover in hypoxia.
  • Carbonic anhydrase IX is a viable target for selective drug delivery to hypoxic tumors.
  • Targeting CAIX offers a promising strategy for overcoming tumor resistance in hypoxic microenvironments.

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