ATF6α promotes prostate cancer progression by enhancing PLA2G4A‐mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis

Abstract

Background Despite the clinical success of androgen receptor (AR)‐targeted therapies, prostate cancer (PCa) inevitably progresses to castration‐resistant prostate cancer (CRPC). Transcription factor 6 α (ATF6α), an effector of the unfolded protein response (UPR) that modulates the cellular response to endoplasmic reticulum (ER) stress, has been linked to tumor development, metastasis, and relapse. However, the role of ATF6α in CRPC remains unclear. Methods The effect of ATF6α on the CRPC‐like phenotype in PCa cells was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)−5‐(3‐carb‐Oxymethoxyphenyl)−2‐(4‐sulfophenyl)−2H‐tetrazolium inner salt (MTS), 5‐Bromo‐2‐deoxyUridine (BrdU) incorporation analysis, and cell death assay. Mechanistically, bioinformatic analysis was utilized to evaluate the potential of PLA2G4A as the target of ATF6α. Moreover, Western blot analysis, real‐time polymerase chain reaction, chromatin immunoprecipitation, arachidonic acid (AA), and prostaglandin E2 (PGE2) assays were performed to identify the regulatory effect of ATF6α on PLA2G4A. Results In this study, we found that the increase of ATF6α expression in response to androgen deprivation generates PCa cells with a CRPC‐like phenotype. PCa cells with high levels of ATF6α expression are resistant to ferroptosis, and genetic and pharmacological inhibition of ATF6α could, therefore, promote the ferroptotic death of tumor cells and delay PCa progression. Molecular analyses linked ATF6α regulation of ferroptosis to the PLA2G4A‐mediated release of AA and the resulting increase in PGE2 production, the latter of which acts as an antiferroptotic factor. Conclusions This study defines ATF6α as a novel antiferroptotic regulator that exacerbates PCa progression. In addition, our data establish ATF6α‐PLA2G4A signaling as an important pathological pathway in PCa, and targeting this pathway may be a novel treatment strategy.

Induction mechanism of ferroptosis: A novel therapeutic target in lung disease

“…Typically, immune balance occurs when a tumor is present; the interaction between ferroptosis and lipid metabolism is very important in tumor immune regulation. Researches have proved that the content of prostaglandin-endoperoxide synthase 2 in tumor cells undergoing ferroptosis is abnormally increased, resulting in the production of the immunosuppressive factor prostaglandin E2, thereby inhibiting the tumor immune function of traditional type 1 dendritic cells, natural killer cells, and cytotoxic T cells (Zhao et al, 2022). In recent years, the relationship between lung cancer and ferroptosis has increasingly studied with a focus on NSCLC and lung adenocarcinoma (Tang et al, 2021;Yao et al, 2021).…”

OIT3 serves as a novel biomarker of hepatocellular carcinoma by mediating ferroptosis via regulating the arachidonic acid metabolism

“…According to various previous studies, leukotriene metabolism, lipoxygenase, phagolysosome, iron ion, arachidonic acid metabolism, and tryptophan could regulate ferroptosis (34)(35)(36)(37)(38). Therefore, we reasoned that OIT3 might be involved in the process of ferroptosis in HCC cell lines.…”

Progression of prostate cancer reprograms MYC-mediated lipid metabolism via lysine methyltransferase 2A

“…The implications of increased lipid metabolism are two-fold: increased synthesis and turnover of membrane lipids associated with cell division, and fatty acid oxidation as an alternative energy source [ 36 ]. With respect to PCa specifically, studies have linked changes in ArA metabolism to PCa development and progression in vitro, with these studies suggesting that ArA is preferentially metabolized by PCa cells [ 37 , 38 ]. However, to the best of our knowledge, the current study is the first to demonstrate an epigenetic link between ArA metabolism, uptake, and MYC activity in human prostate tumors.…”