SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway

Abstract

Pancreatic cancer (PC), a highly lethal malignancy, commonly exhibits metabolic reprogramming that results in therapeutic vulnerabilities. Nevertheless, the mechanisms underlying the impacts of aberrant cholesterol metabolism on PC development and progression remain elusive. In this study, we found that squalene epoxidase (SQLE) is a crucial mediator of cholesterol metabolism in PC growth. We observed a profound upregulation of SQLE in PC tissues, and its high expression was correlated with poor patient outcomes. Our functional experiments demonstrated that SQLE facilitated cell proliferation, induced cell cycle progression, and inhibited apoptosis in vitro, while promoting tumor growth in vivo. Mechanistically, SQLE was found to have a dual role. First, its inhibition led to squalene accumulation-induced endoplasmic reticulum (ER) stress and subsequent apoptosis. Second, it enhanced de novo cholesterol biosynthesis and maintained lipid raft stability, thereby activating the Src/PI3K/Akt signaling pathway. Significantly, employing SQLE inhibitors effectively suppressed PC cell proliferation and xenograft tumor growth. In summary, this study reveals SQLE as a novel oncogene that promotes PC growth by mitigating ER stress and activating lipid raft-regulated Src/PI3K/Akt signaling pathway, highlighting the potential of SQLE as a therapeutic target for PC.

Depletion of squalene epoxidase in synergy with glutathione peroxidase 4 inhibitor RSL3 overcomes oxidative stress resistance in lung squamous cell carcinoma

“…Additionally, it has been proposed that the molecular mechanism driving SQLE expression may involve p53 deletion or mutation [ 23 ]. SQLE also contributes to cholesterol-dependent lipid raft formation and promotes the activation of the Src-PI3K-Akt signaling pathway in pancreatic cancer [ 7 ]. In addition, SQLE plays a cancer-promoting role among other cancer types [ 19 , 34 , 35 ].…”

“…TBF and NB-598, which are widely accessible SQLEi, have been shown to impede the growth and proliferation of HCC, pancreatic cancer and prostate cancer in both in vitro and in vivo studies [ 7 , 8 , 23 , 35 , 36 ]. Our research also confirmed the suppressive effect of TBF and NB-598 on LUSC proliferation and invasion.…”

“…Xu et al . previously showed that squalene epoxidase (SQLE), the enzyme with the second highest rate-limiting contribution to cholesterol synthesis, maintains cholesterol-dependent lipid raft structures and promotes the activation of the Src/PI3K/AKT signalling pathway, which is causally connected with the development of pancreatic cancer [ 7 ]. Moreover, SQLE could promote the development of hepatocellular carcinoma (HCC) through epigenetic reprogramming induced by reactive oxygen species (ROS) accumulation [ 8 ].…”

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB

“…SQLE, as the second key enzyme in cholesterol biosynthesis, catalyzes the initial oxygenation step [ 20 ]. Squalene is converted by SQLE to (S)-2,3-epoxysqualene during cholesterol synthesis, but limited information is currently available regarding the significance of (S)-2,3-epoxysqualene in cancer research [ 21 , 22 ].…”

“…Squalene is converted by SQLE to (S)-2,3-epoxysqualene during cholesterol synthesis, but limited information is currently available regarding the significance of (S)-2,3-epoxysqualene in cancer research [ 21 , 22 ]. SQLE is overexpressed in several cancers and the high expression of SQLE is closely related to the poor prognosis of cancer patients, including CRC [ 20 , 23 ]. It is reported that the poor survival of CRC patients with high SQLE expression is due to its promotion of tumor cell proliferation.…”