Sphingomyelin Metabolism Is a Regulator of K-Ras Function

Dharini van der Hoeven; Kwang-jin Cho; Yong Zhou; Xiaoping Ma; Wei Chen; Ali Naji; Dina Montufar-Solis; Yan Zuo; Sarah E. Kovar; Kandice R. Levental; Jeffrey A. Frost; Ransome van der Hoeven; John F. Hancock

doi:10.1128/MCB.00373-17

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Sphingomyelin Metabolism Is a Regulator of K-Ras Function

Journal article

Peer reviewed

Sphingomyelin Metabolism Is a Regulator of K-Ras Function

Dharini van der Hoeven, Kwang-jin Cho, Yong Zhou, Xiaoping Ma, Wei Chen, Ali Naji, Dina Montufar-Solis, Yan Zuo, Sarah E. Kovar, Kandice R. Levental, …

Molecular and cellular biology, Vol.38(3), e00373-17

02/01/2018

DOI: 10.1128/MCB.00373-17

PMCID: PMC5770534

PMID: 29158292

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https://doi.org/10.1128/MCB.00373-17View

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Abstract

K-Ras must localize to the plasma membrane (PM) for biological activity. We show here that multiple acid sphingomyelinase (ASM) inhibitors, including tricyclic antidepressants, mislocalized phosphatidylserine (PtdSer) and K-RasG12V from the PM, resulting in abrogation of K-RasG12V signaling and potent, selective growth inhibition of mutant K-Ras-transformed cancer cells. Concordantly, in nude mice, the ASM inhibitor fendiline decreased the rate of growth of oncogenic K-Ras-expressing MiaPaCa-2 tumors but had no effect on the growth of the wild-type K-Ras-expressing BxPC-3 tumors. ASM inhibitors also inhibited activated LET-60 (a K-Ras ortholog) signaling in Caenorhabditis elegans , as evidenced by suppression of the induced multivulva phenotype. Using RNA interference against C. elegans genes encoding other enzymes in the sphingomyelin (SM) biosynthetic pathway, we identified 14 enzymes whose knockdown strongly or moderately suppressed the LET-60 multivulva phenotype. In mammalian cells, pharmacological agents that target these enzymes all depleted PtdSer from the PM and caused K-RasG12V mislocalization. These effects correlated with changes in SM levels or subcellular distribution. Selected compounds, including sphingosine kinase inhibitors, potently inhibited the proliferation of oncogenic K-Ras-expressing pancreatic cancer cells. In conclusion, these results show that normal SM metabolism is critical for K-Ras function, which may present therapeutic options for the treatment of K-Ras-driven cancers.

acid sphingomyelinase

K-Ras

sphingomyelin

Details

Title: Subtitle: Sphingomyelin Metabolism Is a Regulator of K-Ras Function
Creators: Dharini van der Hoeven - The University of Texas Health Science Center at Houston
Kwang-jin Cho - Wright State University
Yong Zhou - The University of Texas Health Science Center at Houston
Xiaoping Ma - The University of Texas Health Science Center at Houston
Wei Chen - The University of Texas Health Science Center at Houston
Ali Naji - The University of Texas Health Science Center at Houston
Dina Montufar-Solis - The University of Texas Health Science Center at Houston
Yan Zuo - The University of Texas Health Science Center at Houston
Sarah E. Kovar - Wright State University
Kandice R. Levental - The University of Texas Health Science Center at Houston
Jeffrey A. Frost - The University of Texas Health Science Center at Houston
Ransome van der Hoeven - The University of Texas Health Science Center at Houston
John F. Hancock - The University of Texas Health Science Center at Houston
Resource Type: Journal article
Publication Details: Molecular and cellular biology, Vol.38(3), e00373-17
DOI: 10.1128/MCB.00373-17
PMID: 29158292
PMCID: PMC5770534
NLM abbreviation: Mol Cell Biol
ISSN: 0270-7306
eISSN: 1098-5549
Publisher: Taylor & Francis
Language: English
Date published: 02/01/2018
Academic Unit: Oral Pathology, Radiology and Medicine; Dentistry Administration; Dental Research; Periodontics
Record Identifier: 9984737968002771

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