1660P - Squalene epoxidase promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signalling pathway

Background

Pancreatic cancer (PC) is among the deadliest malignancies with a 5-year survival rate of nearly 12%. Malignant proliferating cancer cells usually exhibit metabolism reprogramming, which is distinct from their normal counterparts, resulting in therapeutic vulnerabilities. However, the underlying mechanisms of aberrant cholesterol metabolism regulating PC progression are poorly understood. In the present study, we aimed to identify and investigate the role of a key cholesterol metabolic enzyme squalene epoxidase (SQLE) in tumorigenesis of PC.

Methods

Integrating analysis of The Cancer Genome Atlas (TCGA) cohort and multiple Gene Expression Omnibus (GEO) datasets was used to find the top up-regulated cholesterol homeostasis-related gene in PC. The IHC staining of tissue microarray composed of human PC samples were used to identify the clinical significance of SQLE in PC patients. The biological functions of SQLE and the potential therapeutic efficiency of SQLE inhibitors were assessed both in vitro and in vivo. Transcriptome analysis, untargeted metabolomics analysis, and related lipid detection were further performed to clarify the molecular mechanism of SQLE on PC development.

Results

We found SQLE expression was highly expressed in PC tissues compared with normal pancreatic tissues, and the upregulated SQLE predicted poor outcomes in PC patients. Additionally, we demonstrated that SQLE promoted the growth of PC both in vitro and in vivo. Mechanistically, inhibition of SQLE caused squalene accumulation-induced endoplasmic reticulum (ER) stress occurrence and subsequent cell apoptosis. Moreover, SQLE increased cholesterol de novo biosynthesis and maintained the stability of lipid rafts, which in turn activated Src/PI3K/Akt signalling. Finally, we found that pharmacological blockade of SQLE with terbinafine or NB-598 profoundly suppressed PC cell proliferation and xenograft tumor growth.

Conclusions

Our findings demonstrated the oncogenic role and tumor promoting mechanism of SQLE in PC. SQLE promotes PC growth by attenuating ER stress and promoting lipid rafts-regulated Src/PI3K/Akt signaling pathway, suggesting SQLE as a potential therapeutic target for PC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This work was supported by the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-002), the National High Level Hospital Clinical Research Funding (2022-PUMCH-D-001), the National Natural Science Foundation of China (82102810) and the fellowship of China Postdoctoral Science Foundation (2021M700501; 2022T150067).

Disclosure

All authors have declared no conflicts of interest.