RT Journal Article
SR Electronic
T1 Targeting plasma membrane phosphatidylserine content to inhibit oncogenic KRAS function
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900431
DO 10.26508/lsa.201900431
VO 2
IS 5
A1 Walaa E Kattan
A1 Wei Chen
A1 Xiaoping Ma
A1 Tien Hung Lan
A1 Dharini van der Hoeven
A1 Ransome van der Hoeven
A1 John F Hancock
YR 2019
UL https://www.life-science-alliance.org/content/2/5/e201900431.abstract
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.