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HRAS‐driven cancer cells are vulnerable to TRPML1 inhibition
Author(s) -
Jung Jewon,
Cho KwangJin,
Naji Ali K,
Clemons Kristen N,
Wong Ching On,
Villanueva Mariana,
Gregory Steven,
Karagas Nicholas E,
Tan Lingxiao,
Liang Hong,
Rousseau Morgan A,
Tomasevich Kelly M,
Sikora Andrew G,
Levental Ilya,
van der Hoeven Dharini,
Zhou Yong,
Hancock John F,
Venkatachalam Kartik
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201846685
Subject(s) - hras , cancer , cancer cell , cancer research , biology , microbiology and biotechnology , chemistry , genetics , colorectal cancer , kras
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.