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

• Main Authors: Jie Gao, Zhengyang Zhang, Yanfang Liu, Zining Zhang, Ming Wang, Aihua Gong, Lin Xia, Xiang Liao, Dongqing Wang, Haitao Zhu
• Format: Article
• Language: English
• Published: Hindawi Limited 2021-01-01
• Series: Oxidative Medicine and Cellular Longevity
• Online Access: http://dx.doi.org/10.1155/2021/6629804

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.