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Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer

Rosa Planells-Cases1, Darius Lutter1, Charlotte Guyader2

  • 1Leibniz-Institut für Molekulare Pharmakologie (FMP) Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany.

The EMBO Journal
|November 5, 2015
PubMed

Insights

Loss of LRRC8A/LRRC8D subunits in volume-regulated anion channels (VRACs) increases resistance to platinum chemotherapy. VRACs mediate cisplatin uptake and apoptosis, impacting tumor cell drug response.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Platinum-based drugs like cisplatin and carboplatin are vital cancer chemotherapeutics.
  • Understanding tumor cell sensitivity to these drugs is crucial for effective cancer treatment.
  • The precise mechanisms governing cellular drug uptake and response remain incompletely understood.

Purpose of the Study:

  • To investigate the role of LRRC8 volume-regulated anion channels (VRACs) in mediating cellular response to platinum-based chemotherapy.
  • To determine the specific LRRC8 subunits involved in cisplatin and carboplatin uptake and their impact on tumor cell sensitivity.
  • To elucidate the dual role of VRACs in drug uptake and apoptosis regulation.

Main Methods:

  • Utilized gene editing techniques to disrupt specific LRRC8 subunits (LRRC8A, LRRC8C, LRRC8D, LRRC8E) in cancer cells.
  • Quantified cisplatin and carboplatin uptake under both isotonic and hypotonic conditions.
  • Assessed drug-induced apoptosis and cellular volume changes in cells with altered LRRC8 channel function.

Main Results:

  • Disruption of LRRC8A and LRRC8D subunits significantly increased resistance to cisplatin and carboplatin.
  • Approximately 50% of cisplatin uptake occurred via LRRC8A/LRRC8D under isotonic conditions, with uptake enhanced by cell swelling.
  • LRRC8A disruption impaired drug-induced apoptosis, potentially by affecting VRAC-dependent cell volume decrease.
  • The LRRC8D subunit incorporation into VRAC enhanced permeability for cisplatin and taurine.

Conclusions:

  • Volume-regulated anion channels (VRACs), particularly those containing LRRC8D, play a critical dual role in cancer chemotherapy by mediating platinum drug uptake and facilitating apoptosis.
  • LRRC8A and LRRC8D subunits are key determinants of cisplatin and carboplatin sensitivity in tumor cells.
  • Targeting LRRC8D-containing VRACs may offer a novel strategy to enhance the efficacy of platinum-based chemotherapies in cancer treatment.
Keywords:
VSOACVSORchloride channelhaploid cell screenswelling‐activated

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