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Transient receptor potential channel TRPC5 is essential for P-glycoprotein induction in drug-resistant cancer cells.


Proc Natl Acad Sci U S A. 2012 Sep 17;


Authors: Ma X, Cai Y, He D, Zou C, Zhang P, Lo CY, Xu Z, Chan FL, Yu S, Chen Y, Zhu R, Lei J, Jin J, Yao X


Abstract

An attractive strategy to overcome multidrug resistance in cancer chemotherapy is to suppress P-glycoprotein (P-gp), which is a pump overproduced in cancer cells to remove cytotoxic drugs from cells. In the present study, a Ca(2+)-permeable channel TRPC5 was found to be overproduced together with P-gp in adriamycin-resistant breast cancer cell line MCF-7/ADM. Suppressing TRPC5 activity/expression reduced the P-gp induction and caused a remarkable reversal of adriamycin resistance in MCF-7/ADM. In an athymic nude mouse model of adriamycin-resistant human breast tumor, suppressing TRPC5 decreased the growth of tumor xenografts. Nuclear factor of activated T cells isoform c3 (NFATc3) was the transcriptional factor that links the TRPC5 activity to P-gp production. Together, we demonstrated an essential role of TRPC5-NFATc3-P-gp signaling cascade in P-gp induction in drug-resistant cancer cells.

PMID: 22988121 [PubMed - as supplied by publisher]