The lysosomal TRPML1 channel regulates triple negative breast cancer development by promoting mTORC1 and purinergic signaling pathways.

Autor: Xu M; Department of Physiology and Biophysics, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada; Department of Physiology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, China., Almasi S; Department of Biology, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada., Yang Y; Department of Physiology and Biophysics, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada., Yan C; Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada., Sterea AM; Department of Physiology and Biophysics, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada., Rizvi Syeda AK; Department of Physiology and Biophysics, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada., Shen B; Department of Physiology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, China., Richard Derek C; Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada., Huang P; College of Basic Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, China., Gujar S; Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada., Wang J; Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada., Zong WX; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway NJ08854, USA., Trebak M; Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey PA 17033, USA., El Hiani Y; Department of Physiology and Biophysics, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada. Electronic address: yassine.elhiani@Dal.Ca., Dong XP; Department of Physiology and Biophysics, Dalhousie University, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada; Department of Physiology, School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, China. Electronic address: xpdong@dal.ca.
Jazyk: angličtina
Zdroj: Cell calcium [Cell Calcium] 2019 May; Vol. 79, pp. 80-88. Date of Electronic Publication: 2019 Mar 02.
DOI: 10.1016/j.ceca.2019.02.010
Abstrakt: The triple-negative breast cancer (TNBC) that comprises approximately 10%-20% of breast cancers is an aggressive subtype lacking effective therapeutics. Among various signaling pathways, mTORC1 and purinergic signals have emerged as potentially fruitful targets for clinical therapy of TNBC. Unfortunately, drugs targeting these signaling pathways do not successfully inhibit the progression of TNBC, partially due to the fact that these signaling pathways are essential for the function of all types of cells. In this study, we report that TRPML1 is specifically upregulated in TNBCs and that its genetic downregulation and pharmacological inhibition suppress the growth of TNBC. Mechanistically, we demonstrate that TRPML1 regulates TNBC development, at least partially, through controlling mTORC1 activity and the release of lysosomal ATP. Because TRPML1 is specifically activated by cellular stresses found in tumor microenvironments, antagonists of TRPML1 could represent anticancer drugs with enhanced specificity and potency. Our findings are expected to have a major impact on drug targeting of TNBCs.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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