Targeting polyunsaturated fatty acids desaturase FADS1 inhibits renal cancer growth via ATF3-mediated ER stress response
Gioia Heravi, Zhenjie Liu, Mackenzie K. Herroon, Alexis Wilson, Yang-Yi Fan, Yang Jiang, Nivisa Vakeesan, Tao Li, Zheyun Peng, Kezhong Zhang, Jing Li, Robert S. Chapkin, Izabela Podgorski, Wanqing Liu
Abstract
Fatty Acid Desaturase 1 (FADS1) is a rate-limiting enzyme controlling the bioproduction of long-chain polyunsaturated fatty acids (PUFAs). Increasing studies suggest that FADS1 is a potential cancer target. Our previous research has demonstrated the significant role of FADS1 in cancer biology and patient survival, especially in kidney cancers. We aim to explore the underlying mechanism in this study. We found that pharmacological inhibition or knockdown of the expression of FADS1 significantly reduced the intracellular conversion of long-chain PUFAs, effectively inhibits renal cancer cell proliferation, and induces cell cycle arrest. The stable knockdown of FADS1 also significantly inhibits tumor formation in vivo . Mechanistically, we showed that while FADS1 inhibition induces endoplasmic reticulum (ER) stress, FADS1 expression is augmented by ER-stress inducer, suggesting a necessary role of PUFA production in response to ER stress. FADS1-inhibition sensitized cellular response to ER stress inducers, leading to cell apoptosis. Also, FADS1 inhibition-induced ER stress leads to activation of the PERK/eIF2α/ATF4/ATF3 pathway. Inhibiting PERK or knockdown of ATF3 rescued FADS1 inhibition-induced ER stress and cell growth suppression, while ATF3-overexpression aggravates the FADS1 inhibition-induced cell growth suppression and leads to cell death. Metabolomic analysis revealed that FADS1 inhibition results in decreased level of UPD-N-Acetylglucosamine, a critical mediator of the unfolded protein response, as well as impaired biosynthesis of nucleotides, possibly accounting for the cell cycle arrest. Our findings suggest that PUFA desaturation is crucial for rescuing cancer cells from persistent ER stress, supporting FADS1 as a new therapeutic target. • FADS1 inhibition suppresses renal cancer cell proliferation and tumor growth. • FADS1 inhibition induces ER stress via the PERK/eIF2α/ATF4/ATF3 pathway. • Targeting FADS1 sensitizes cancer cells to ER stress inducers, leading to apoptosis. • ATF3 is a key mediator for the FADS1 inhibition-induced cancer cell growth suppression. • FADS1 inhibition disrupts metabolic pathways of nucleotide and protein metabolism.