%0 Journal Article
%T Lysophosphatidylcholine acyltransferase 1 suppresses nanoclustering and function of KRAS.
%A Arora N
%A Liang H
%A Yao W
%A Ying H
%A Liu J
%A Zhou Y
%J bioRxiv
%V 0
%N 0
%D 2024 Jun 2
%M 38853864
暂无%R 10.1101/2024.05.30.596653
%X KRAS is frequently mutated in cancer, contributing to 20% of all human cancer especially pancreatic, colorectal and lung cancer. Signaling of the constitutively active KRAS oncogenic mutants is mostly compartmentalized to proteolipid nanoclusters on the plasma membrane (PM). Signaling nanoclusters of many KRAS mutants selectively enrich phosphatidylserine (PS) lipids with unsaturated sn-2 acyl chains, but not the fully saturated PS species. Thus, remodeling PS acyl chains may suppress KRAS oncogenesis. Lysophosphatidylcholine acyltransferases (LPCATs) remodel sn-2 acyl chains of phospholipids, with LPCAT1 preferentially generating the fully saturated lipids. Here, we show that stable expression of LPCAT1 depletes major PS species with unsaturated sn-2 chains while decreasing minor phosphatidylcholine (PC) species with the corresponding acyl chains. LPCAT1 expression more effectively disrupts the nanoclustering of oncogenic GFP-KRASG12V, which is restored by acute addback of exogenous unsaturated PS. LPCAT1 expression compromises signaling and oncogenic activities of the KRAS-dependent pancreatic tumor lines. LPCAT1 expression sensitizes human pancreatic tumor MiaPaCa-2 cells to KRASG12C specific inhibitor, Sotorasib. Statistical analyses of patient data further reveal that pancreatic cancer patients with KRAS mutations express less LPCAT1. Higher LPCAT1 expression also improves survival probability of pancreatic and lung adenocarcinoma patients with KRAS mutations. Thus, PS acyl chain remodeling selectively suppresses KRAS oncogenesis.