ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability

Abstract

Reprogramming of lipid metabolism, which modulates energy utilization and cell signaling, maintains cell survival and promotes cancer metastasis in cancer cells. Ferroptosis is a type of cell necrosis caused by an overload of lipid oxidation, which has been demonstrated to be involved in cancer cell metastasis. However, the mechanism by which fatty acid metabolism regulates the anti-ferroptosis signaling pathways is not fully understood. The formation of ovarian cancer spheroids helps to counteract the hostile microenvironment of the peritoneal cavity with low oxygen, shortage of nutrients, and subjected to platinum therapy. Previously, we demonstrated that Acyl-CoA synthetase long-chain family member 1 (ACSL1) promotes cell survival and peritoneal metastases in ovarian cancer, but the mechanism is still not well elucidated. In this study, we demonstrate that the formation of spheroids and under exposure to platinum chemotherapy increased the levels of anti-ferroptosis proteins as well as ACSL1. Inhibition of ferroptosis can enhance spheroid formation and vice versa. Genetic manipulation of ACSL1 expression showed that ACSL1 reduced the level of lipid oxidation and increased the resistance to cell ferroptosis. Mechanistically, ACSL1 increased the N-myristoylation of ferroptosis suppressor 1 (FSP1), resulting in the inhibition of its degradation and translocation to the cell membrane. The increase in myristoylated FSP1 functionally counteracted oxidative stress-induced cell ferroptosis. Clinical data also suggested that ACSL1 protein was positively correlated with FSP1 and negatively correlated with the ferroptosis markers 4-HNE and PTGS2. In conclusion, this study demonstrated that ACSL1 enhances antioxidant capacity and increases ferroptosis resistance by modulating the myristoylation of FSP1.

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…Strikingly, resistance to ferroptosis reduced the sensitivity of ovarian cancer cells to platinum (Q. Zhang, Li, et al, 2023). These findings imply that interventions targeting ferroptosis may be promising strategies for cancer management.…”

“…Furthermore, epithelial membrane protein 1 (EMP1) deficiency promoted the expression of solute carrier family 7 member 11 (SLC7A11) by activating the peroxisome proliferator‐activated receptor‐γ (PPARG) signaling pathway, which enhanced cancer metastasis via inhibiting ferroptosis in bladder cancer cells (S. Liu, Shi, et al, 2022). Strikingly, resistance to ferroptosis reduced the sensitivity of ovarian cancer cells to platinum (Q. Zhang, Li, et al, 2023). These findings imply that interventions targeting ferroptosis may be promising strategies for cancer management.…”

Advances in Ferroptosis-Inducing Agents by Targeted Delivery System in Cancer Therapy

“…This incorporation interferes with the formation of PUFA phospholipids and protects cells from iron-induced apoptosis. 69 …”

Biological Action of Singlet Molecular Oxygen from the Standpoint of Cell Signaling, Injury and Death

“…The accumulation of P-LOOH along with iron may consequently induce cell rupture [77], which is typically observed in ferroptosis [23,24]. Although the accumulation of lipid-derived aldehydes, such as 4-hydroxyl nonenal and malondialdehyde, is considered to be a hallmark of ferroptosis [78,79], it is not clear at this moment if the β-scission of P-LOOH is essential or not for executing cell death. LOOH produced by 1 O 2 during PDT along with iron may produce lipid radicals LOO• and then initiate a chain reaction, which leads to cell death [80].…”