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EMBO Rep. 2019 Apr;20(4). pii: e46685. doi: 10.15252/embr.201846685. Epub 2019 Feb 20.

HRAS-driven cancer cells are vulnerable to TRPML1 inhibition.

Author information

1
Department of Integrative Biology and Pharmacology, McGovern Medical School, the University of Texas Health Sciences Center (UTHealth), Houston, TX, USA.
2
Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA.
3
Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center, Houston, TX, USA.
4
Graduate Program in Biochemistry and Cell Biology, MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
5
Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA.
6
Patient Derived Xenografts and Advanced in vivo Models Core Facility, Baylor College of Medicine, Houston, TX, USA.
7
Department of Integrative Biology and Pharmacology, McGovern Medical School, the University of Texas Health Sciences Center (UTHealth), Houston, TX, USA Kartik.venkatachalam@uth.tmc.edu.

Abstract

By serving as intermediaries between cellular metabolism and the bioenergetic demands of proliferation, endolysosomes allow cancer cells to thrive under normally detrimental conditions. Here, we show that an endolysosomal TRP channel, TRPML1, is necessary for the proliferation of cancer cells that bear activating mutations in HRAS Expression of MCOLN1, which encodes TRPML1, is significantly elevated in HRAS-positive tumors and inversely correlated with patient prognosis. Concordantly, MCOLN1 knockdown or TRPML1 inhibition selectively reduces the proliferation of cancer cells that express oncogenic, but not wild-type, HRAS Mechanistically, TRPML1 maintains oncogenic HRAS in signaling-competent nanoclusters at the plasma membrane by mediating cholesterol de-esterification and transport. TRPML1 inhibition disrupts the distribution and levels of cholesterol and thereby attenuates HRAS nanoclustering and plasma membrane abundance, ERK phosphorylation, and cell proliferation. These findings reveal a selective vulnerability of HRAS-driven cancers to TRPML1 inhibition, which may be leveraged as an actionable therapeutic strategy.

KEYWORDS:

HRAS ; TRPML1; cancer; cholesterol; endolysosomes

PMID:
30787043
PMCID:
PMC6446245
[Available on 2020-04-01]
DOI:
10.15252/embr.201846685

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