PT  - JOURNAL ARTICLE
AU  - Walaa E Kattan
AU  - Wei Chen
AU  - Xiaoping Ma
AU  - Tien Hung Lan
AU  - Dharini van der Hoeven
AU  - Ransome van der Hoeven
AU  - John F Hancock
TI  - Targeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function
AID  - 10.26508/lsa.201900431
DP  - 2019 Oct 01
TA  - Life Science Alliance
PG  - e201900431
VI  - 2
IP  - 5
4099  - https://www.life-science-alliance.org/content/2/5/e201900431.short
4100  - https://www.life-science-alliance.org/content/2/5/e201900431.full
SO  - Life Sci. Alliance2019 Oct 01; 2
AB  - 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.