TY - JOUR
T1 - The lysosomal TRPML1 channel regulates triple negative breast cancer development by promoting mTORC1 and purinergic signaling pathways
AU - Xu, Mengnan
AU - Almasi, Shekoufeh
AU - Yang, Yiming
AU - Yan, Chi
AU - Sterea, Andra Mihaela
AU - Rizvi Syeda, Alia Kazim
AU - Shen, Bing
AU - Richard Derek, Clements
AU - Huang, Peng
AU - Gujar, Shashi
AU - Wang, Jun
AU - Zong, Wei Xing
AU - Trebak, Mohamed
AU - El Hiani, Yassine
AU - Dong, Xian Ping
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ceca.2019.02.010
DO - 10.1016/j.ceca.2019.02.010
M3 - Article
C2 - 30889511
AN - SCOPUS:85063011838
SN - 0143-4160
VL - 79
SP - 80
EP - 88
JO - Cell Calcium
JF - Cell Calcium
ER -