2. Academic Validation
  3. The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing

The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing

  • Cell Rep. 2023 Oct 31;42(11):113347. doi: 10.1016/j.celrep.2023.113347.
Dimpi Mukhopadhyay 1,  Hira Lal Goel 1,  Choua Xiong 1,  Shivam Goel 1,  Ayush Kumar 1,  Rui Li 1,  Lihua Julie Zhu 1,  Jennifer L Clark 2,  Michael A Brehm 3,  Arthur M Mercurio 4
Affiliations

Affiliations

  • 1 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
  • 2 Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
  • 3 Department of Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
  • 4 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA. Electronic address: arthur.mercurio@umassmed.edu.
PMID: 37910503 DOI: 10.1016/j.celrep.2023.113347
Abstract

Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast Cancer Stem Cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate Integrin α6 mRNA splicing. Specifically, TRPC6-mediated calcium entry represses the epithelial splicing factor ESRP1 (epithelial splicing regulatory protein 1), which enables expression of the Integrin α6B splice variant. TRPC6 and α6B function in tandem to facilitate stemness and persistence by activating TAZ and, consequently, repressing Myc. Therapeutic inhibition of TRPC6 sensitizes triple-negative breast Cancer (TNBC) cells and tumors to chemotherapy by targeting the splicing of α6 Integrin mRNA and inducing Myc. These data reveal a Ca2+-dependent mechanism of chemotherapy-induced persistence, which is amenable to therapy, that involves Integrin mRNA splicing.

Keywords

CP: Cancer; chemoresistance, breast cancer, calcium signaling, mRNA splicing, integrins..

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