HRAS-driven cancer cells are vulnerable to TRPML1 inhibition

Jewon Jung; Kwang-Jin Cho; Ali K Naji; Kristen N Clemons; Ching On Wong; Mariana Villanueva; Steven Gregory; Nicholas E Karagas; Lingxiao Tan; Hong Liang; Morgan A Rousseau; Kelly M Tomasevich; Andrew G Sikora; Ilya Levental; Dharini van der Hoeven; Yong Zhou; John F Hancock; Kartik Venkatachalam

doi:10.15252/embr.201846685

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HRAS-driven cancer cells are vulnerable to TRPML1 inhibition

Journal article

Peer reviewed

HRAS-driven cancer cells are vulnerable to TRPML1 inhibition

Jewon Jung, Kwang-Jin Cho, Ali K Naji, Kristen N Clemons, Ching On Wong, Mariana Villanueva, Steven Gregory, Nicholas E Karagas, Lingxiao Tan, Hong Liang, …

EMBO reports, Vol.20(4), p.n/a

04/2019

DOI: 10.15252/embr.201846685

PMID: 30787043

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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 Expression of , which encodes TRPML1, is significantly elevated in -positive tumors and inversely correlated with patient prognosis. Concordantly, knockdown or TRPML1 inhibition selectively reduces the proliferation of cancer cells that express oncogenic, but not wild-type, 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 -driven cancers to TRPML1 inhibition, which may be leveraged as an actionable therapeutic strategy.

Animals

Calcium - metabolism

Calcium Signaling

Cell Membrane - metabolism

Cell Proliferation

Drosophila

Endosomes - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism

Gene Expression

Gene Regulatory Networks

Humans

Lysosomes - metabolism

Models, Biological

Mutation

Neoplasms - genetics

Neoplasms - metabolism

Neoplasms - mortality

Neoplasms - pathology

Phosphorylation

Prognosis

Proto-Oncogene Proteins p21(ras) - genetics

Proto-Oncogene Proteins p21(ras) - metabolism

Signal Transduction

Transcriptome

Transient Receptor Potential Channels - antagonists & inhibitors

Transient Receptor Potential Channels - genetics

Transient Receptor Potential Channels - metabolism

Details

Title: Subtitle: HRAS-driven cancer cells are vulnerable to TRPML1 inhibition
Creators: Jewon Jung - The University of Texas Health Science Center at Houston
Kwang-Jin Cho - Wright State University
Ali K Naji - The University of Texas Health Science Center at Houston
Kristen N Clemons - The University of Texas MD Anderson Cancer Center
Ching On Wong - Department of Integrative Biology and Pharmacology, McGovern Medical School, the University of Texas Health Sciences Center (UTHealth), Houston, TX, USA
Mariana Villanueva - Baylor College of Medicine
Steven Gregory - The University of Texas MD Anderson Cancer Center
Nicholas E Karagas - The University of Texas MD Anderson Cancer Center
Lingxiao Tan - The University of Texas MD Anderson Cancer Center
Hong Liang - Department of Integrative Biology and Pharmacology, McGovern Medical School, the University of Texas Health Sciences Center (UTHealth), Houston, TX, USA
Morgan A Rousseau - The University of Texas Health Science Center at Houston
Kelly M Tomasevich - The University of Texas Health Science Center at Houston
Andrew G Sikora - Baylor College of Medicine
Ilya Levental - The University of Texas MD Anderson Cancer Center
Dharini van der Hoeven - The University of Texas Health Science Center at Houston
Yong Zhou - The University of Texas Health Science Center at Houston
John F Hancock - The University of Texas Health Science Center at Houston
Kartik Venkatachalam - The University of Texas MD Anderson Cancer Center
Resource Type: Journal article
Publication Details: EMBO reports, Vol.20(4), p.n/a
DOI: 10.15252/embr.201846685
PMID: 30787043
ISSN: 1469-221X
eISSN: 1469-3178
Grant note: R00 CA188593 / NCI NIH HHS R01 NS081301 / NINDS NIH HHS P30 CA125123 / NCI NIH HHS R21 NS094860 / NINDS NIH HHS
Language: English
Date published: 04/2019
Academic Unit: Oral Pathology, Radiology and Medicine; Dentistry Administration
Record Identifier: 9985157464702771

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