TY - JOUR

T1 - Dual role of LRRC8A-containing transporters on cisplatin resistance in human ovarian cancer cells

AU - Sørensen, Belinda Halling

AU - Dam, Celina Støving

AU - Stürup, Stefan

AU - Lambert, Ian Henry

N1 - Copyright © 2016 Elsevier Inc. All rights reserved.

PY - 2016

Y1 - 2016

N2 - Acquired resistance to chemotherapeutic drugs in cancer cells can reflect an ability to limit cellular drug availability, to repair drug induced DNA damage, and to limit initiation/progression of cell death (apoptosis). The leucine-rich-repeat-containing 8A (LRRC8A) protein is an essential component of volume sensitive channels for organic osmolytes (VSOAC) and volume regulated anion channels (VRAC), which are activated during the apoptotic process. Here we illustrate that cisplatin resistance in human ovarian cancer cells (A2780) correlates with a reduced expression of LRRC8A and copper transporter receptor 1 (CTR1), as well as a concomitant increased expression of copper-transporting P-type ATPases (ATP7A/ATP7B). We also find that cisplatin (Pt) accumulation correlates with LRRC8A protein expression and channel activity, i.e., the cellular Pt content is high when VSOAC is activated by depolarization of the plasma membrane or hypoosmotic cell swelling, and reduced when channel activity/LRRC8A expression is reduced by genetically silencing/pharmacological inhibition, or the cells have acquired a resistant phenotype with low LRRC8A protein expression. It is suggested that reduced LRRC8A expression in cisplatin-resistant A2780 cells ensures cell survival through limitation in cisplatin accumulation and a concomitant reduction in osmolytes loss via VSOAC/VRAC and hence instigation of the apoptotic process.

AB - Acquired resistance to chemotherapeutic drugs in cancer cells can reflect an ability to limit cellular drug availability, to repair drug induced DNA damage, and to limit initiation/progression of cell death (apoptosis). The leucine-rich-repeat-containing 8A (LRRC8A) protein is an essential component of volume sensitive channels for organic osmolytes (VSOAC) and volume regulated anion channels (VRAC), which are activated during the apoptotic process. Here we illustrate that cisplatin resistance in human ovarian cancer cells (A2780) correlates with a reduced expression of LRRC8A and copper transporter receptor 1 (CTR1), as well as a concomitant increased expression of copper-transporting P-type ATPases (ATP7A/ATP7B). We also find that cisplatin (Pt) accumulation correlates with LRRC8A protein expression and channel activity, i.e., the cellular Pt content is high when VSOAC is activated by depolarization of the plasma membrane or hypoosmotic cell swelling, and reduced when channel activity/LRRC8A expression is reduced by genetically silencing/pharmacological inhibition, or the cells have acquired a resistant phenotype with low LRRC8A protein expression. It is suggested that reduced LRRC8A expression in cisplatin-resistant A2780 cells ensures cell survival through limitation in cisplatin accumulation and a concomitant reduction in osmolytes loss via VSOAC/VRAC and hence instigation of the apoptotic process.

U2 - 10.1016/j.jinorgbio.2016.04.004

DO - 10.1016/j.jinorgbio.2016.04.004

M3 - Journal article

C2 - 27112899

VL - 160

SP - 287

EP - 295

JO - Journal of Inorganic Biochemistry

JF - Journal of Inorganic Biochemistry

SN - 0162-0134

ER -