Stearoyl-CoA desaturase-1 mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis.

Ling Chen,Longhe Yang,Yifeng Tian,Yan Qiu,Funan Qiu,Jie Ren,Jin Fu,Yanting Li,Yuhang Li,Zuguo Liu

doi:10.1038/srep19665

Abstract

Inhibition of stearoyl-CoA desaturase 1 (SCD1) has been found to effectively suppress tumor cell proliferation and induce apoptosis in numerous neoplastic lesions. However, mechanism underlying SCD1-mediated anti-tumor effect has maintained unclear. Herein, we reported endo-lipid messenger ceramides played a critical role in tumor fate modulated by SCD1 inhibition. In vitro study in colorectal cancer cells demonstrated inhibition of SCD1 activity promoted apoptosis attributed to mitochondria dysfunctions, upregulation of reaction oxygen species (ROS), alteration of mitochondrial transmembrane potential and translocation of mitochondrial protein cytochrome C. While these effects were mediated by intracellular ceramide signals through induction of ceramide biosynthesis, rather than exclusive SFA accumulation. In vivo study in xenograft colorectal cancer mice showed pharmacologic administration of SCD1 inhibitor A939 significantly delayed tumor growth, which was reversed by L-cycloserine, an inhibitor of ceramide biosynthesis. These results depicted the cross-talk of SCD1-mediated lipid pathway and endo-ceramide biosynthesis pathway, indicating roles of ceramide signals in SCD1-mediated anti-tumor property.

Highlights

By a fatty acyl base with varying carbon chain length and generated by de novo synthesis from palmitoyl-CoA and L-serine[18]
It is intriguing to raise a question: what is the linkage between cellular ceramide signals and SCD1 pathway? Our studies demonstrated that the inhibition of SCD1 activity caused the increase of endogenous cellular SFA levels in both colorectal and ovarian cancer cells, while the increased ceramide levels could be observed only in colorectal cancer cells accompanying with the suppression of cell proliferation
Consistent with previous reports, our data showed an increase of SCD1 mRNA, protein and activity expressions in tumor tissues of colorectal cancer patients (Fig. 1a–c), which suggested that inhibition of SCD1 may be a promising strategy for colorectal cancer control

Summary

Introduction

By a fatty acyl base with varying carbon chain length and generated by de novo synthesis from palmitoyl-CoA and L-serine[18]. To gain the information of SCD1 and endo-ceramide signals in tumor development, we analyzed the expression levels of them in tumor tissues obtained from colorectal cancer patients.

Results

Conclusion