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.
Abstract:
The small GTPase KRAS, which is frequently mutated in human cancers, must be localized to the plasma membrane (PM) for biological activity. We recently showed that the KRAS C-terminal membrane anchor exhibits exquisite lipid-binding specificity for select species of phosphatidylserine (PtdSer). We, therefore, investigated whether reducing PM PtdSer content is sufficient to abrogate KRAS oncogenesis. Oxysterol-related binding proteins ORP5 and ORP8 exchange PtdSer synthesized in the ER for phosphatidyl-4-phosphate synthesized in the PM. We show that depletion of ORP5 or ORP8 reduced PM PtdSer levels, resulting in extensive mislocalization of KRAS from the PM. Concordantly, ORP5 or ORP8 depletion significantly reduced proliferation and anchorage-independent growth of multiple KRAS-dependent cancer cell lines, and attenuated KRAS signaling in vivo. Similarly, functionally inhibiting ORP5 and ORP8 by inhibiting PI4KIIIα-mediated synthesis of phosphatidyl-4-phosphate at the PM selectively inhibited the growth of KRAS-dependent cancer cell lines over normal cells. Inhibiting KRAS function through regulating PM lipid PtdSer content may represent a viable strategy for KRAS-driven cancers.
Insights
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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