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

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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 1 2019

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Triple Negative Breast Neoplasms
Drug Delivery Systems
Tumor Microenvironment
Down-Regulation
Adenosine Triphosphate
mechanistic target of rapamycin complex 1
Pharmacology
Breast Neoplasms
Therapeutics
Growth
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Xu, Mengnan ; Almasi, Shekoufeh ; Yang, Yiming ; Yan, Chi ; Sterea, Andra Mihaela ; Rizvi Syeda, Alia Kazim ; Shen, Bing ; Richard Derek, Clements ; Huang, Peng ; Gujar, Shashi ; Wang, Jun ; Zong, Wei Xing ; Trebak, Mohamed ; El Hiani, Yassine ; Dong, Xian Ping. / The lysosomal TRPML1 channel regulates triple negative breast cancer development by promoting mTORC1 and purinergic signaling pathways. In: Cell Calcium. 2019 ; Vol. 79. pp. 80-88.
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Xu, M, Almasi, S, Yang, Y, Yan, C, Sterea, AM, Rizvi Syeda, AK, Shen, B, Richard Derek, C, Huang, P, Gujar, S, Wang, J, Zong, WX, Trebak, M, El Hiani, Y & Dong, XP 2019, 'The lysosomal TRPML1 channel regulates triple negative breast cancer development by promoting mTORC1 and purinergic signaling pathways', Cell Calcium, vol. 79, pp. 80-88. https://doi.org/10.1016/j.ceca.2019.02.010

The lysosomal TRPML1 channel regulates triple negative breast cancer development by promoting mTORC1 and purinergic signaling pathways. / Xu, Mengnan; Almasi, Shekoufeh; Yang, Yiming; Yan, Chi; Sterea, Andra Mihaela; Rizvi Syeda, Alia Kazim; Shen, Bing; Richard Derek, Clements; Huang, Peng; Gujar, Shashi; Wang, Jun; Zong, Wei Xing; Trebak, Mohamed; El Hiani, Yassine; Dong, Xian Ping.

In: Cell Calcium, Vol. 79, 01.05.2019, p. 80-88.

Research output: Contribution to journalArticle

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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

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