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

Mengnan Xu, Shekoufeh Almasi, Yiming Yang, Chi Yan, Andra Mihaela Sterea, Alia Kazim Rizvi Syeda, Bing Shen, Clements Richard Derek, Peng Huang, Shashi Gujar, Jun Wang, Wei Xing Zong, Mohamed Trebak, Yassine El Hiani, Xian Ping Dong

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)80-88
Number of pages9
JournalCell Calcium
Volume79
DOIs
StatePublished - May 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Xu, M., Almasi, S., Yang, Y., Yan, C., Sterea, A. M., Rizvi Syeda, A. K., Shen, B., Richard Derek, C., Huang, P., Gujar, S., Wang, J., Zong, W. X., Trebak, M., El Hiani, Y., & Dong, X. P. (2019). The lysosomal TRPML1 channel regulates triple negative breast cancer development by promoting mTORC1 and purinergic signaling pathways. Cell Calcium, 79, 80-88. https://doi.org/10.1016/j.ceca.2019.02.010