Stearoyl-CoA Desaturase 1 Potentiates Hypoxic plus Nutrient-Deprived Pancreatic Cancer Cell Ferroptosis Resistance

Jie Gao,Haitao Zhu,Zhengyang Zhang,Xiang Liao,Aihua Gong,Zining Zhang,Yanfang Liu,Ming Wang,Lin Xia,Dongqing Wang,Li Yang

doi:10.1155/2021/6629804

Abstract

Hypoxia and nutrient starvation (H/NS) microenvironment, a notable characteristic of pancreatic carcinoma, plays a critical role in cell death resistance and tumor recurrence. However, its role in ferroptosis remains to be classified. Here, we found that H/NS contributed to the pancreatic cancer cell ferroptosis resistance depending on the altered intracellular lipid compositions. Mechanistically, H/NS induced the upregulation of stearoyl-CoA desaturase 1 (SCD1), which promoted monounsaturated fatty acids (MUFAs) synthesis and protected against lipid peroxidation. Surprisingly, SCD1 showed a strong correlation with antiferroptosis gene expression. Moreover, short-hairpin RNA-based knockdown of SCD1 enhanced erastin-induced ferroptosis in vitro under H/NS. Finally, our results demonstrate the synergistic effect of erastin and A939572, a special SCD1 inhibitor, in dictating pancreatic carcinoma subcutaneous ferroptotic death. Taken together, our findings reveal a new role of the H/NS microenvironment against ferroptosis and suggest a potential therapeutic strategy for overcoming ferroptosis resistance in pancreatic cancer cells.

Highlights

Due to the imbalance of unlimited proliferation of cancer cells and poor supplement of blood vessels, hypoxia and nutrient starvation (H/Nutrient starvation (NS)) has been recognized as the most important characteristic of pancreatic carcinoma microenvironment [1, 2]
SCD1mediated accumulation of Monounsaturated fatty acids (MUFAs) is involved in protecting PDAC cells from ferroptosis under hypoxia and nutrient starvation (H/NS) condition
Our results show that pancreatic cancer cells under H/NS condition were significantly resistant to the ferroptosis inducers, a novel form of tumor-suppressor function for cancer therapy

Summary

Introduction

Due to the imbalance of unlimited proliferation of cancer cells and poor supplement of blood vessels, hypoxia and nutrient starvation (H/NS) has been recognized as the most important characteristic of pancreatic carcinoma microenvironment [1, 2]. It is necessary to investigate the mechanisms underlying the H/NS microenvironment mediating the cancer cell death resistance. Under H/NS, cancer cells mostly depended on metabolism reprogramming, such as elevated de novo synthesis of fatty acids (FAs), for the sake of thriving [6, 7]. Monounsaturated fatty acids (MUFAs) block the lipid ROS accumulation on the plasma membrane and further induce the ferroptosis-resistant state [10]. Stearoyl-CoA desaturase 1 (SCD1), a critical regulator of de novo synthesis, catalyzes the desaturation of saturated fatty acids (SFAs) to MUFAs [11]. These findings suggested that SCD1 may be involved in H/NS microenvironment-induced ferroptotic cell death resistance in cancer cells

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Conclusion