Targeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function
Walaa E Kattan1,2, Wei Chen1, Xiaoping Ma1
1Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.
Life Science Alliance
|August 28, 2019
Summary
Reducing plasma membrane phosphatidylserine (PtdSer) disrupts KRAS oncogenesis. Depleting ORP5 or ORP8 proteins lowers PtdSer, mislocalizing KRAS and inhibiting cancer cell growth, offering a new therapeutic strategy.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- KRAS mutations drive human cancers, requiring plasma membrane localization for activity.
- KRAS C-terminal anchor specifically binds phosphatidylserine (PtdSer) at the plasma membrane.
- Oxysterol-binding proteins (ORPs) like ORP5 and ORP8 regulate PtdSer levels at the plasma membrane.
Purpose of the Study:
- To investigate if reducing plasma membrane PtdSer can inhibit KRAS-driven oncogenesis.
- To determine the role of ORP5 and ORP8 in KRAS localization and cancer cell proliferation.
Main Methods:
- Depletion of ORP5 or ORP8 using genetic techniques.
- Assessment of KRAS localization to the plasma membrane.
- Measurement of cancer cell proliferation and anchorage-independent growth.
- Inhibition of PI4KIIIα to block phosphatidyl-4-phosphate synthesis.
Main Results:
- ORP5 or ORP8 depletion significantly reduced plasma membrane PtdSer levels.
- KRAS was extensively mislocalized from the plasma membrane upon ORP5/ORP8 depletion.
- Depletion of ORP5/ORP8 or inhibition of PI4KIIIα selectively reduced proliferation of KRAS-dependent cancer cells.
- KRAS signaling was attenuated in vivo following ORP5/ORP8 depletion.
Conclusions:
- Plasma membrane PtdSer content is critical for KRAS oncogenesis.
- Targeting ORP5/ORP8 or related lipid metabolism pathways offers a potential therapeutic strategy for KRAS-driven cancers.
- Modulating plasma membrane lipid composition presents a novel approach to inhibit KRAS function.
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