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

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...

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Vydáno v:The Prostate Ročník 82; číslo 5; s. 617 - 629
Hlavní autoři: Zhao, Ru, Lv, Ye, Feng, Tingting, Zhang, Ruojia, Ge, Luna, Pan, Jihong, Han, Bo, Song, Guanhua, Wang, Lin
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Wiley Subscription Services, Inc 01.04.2022
John Wiley and Sons Inc
Témata:
Androgen Antagonists - therapeutic use
Androgen receptors
Androgens
Arachidonic acid
Arachidonic Acid - therapeutic use
ATF6α
Castration
Cell death
Cell Line, Tumor
Chromatin
CRPC
Dinoprostone
Endoplasmic reticulum
Ferroptosis
Group IV Phospholipases A2
Humans
Immunoprecipitation
Male
Metastases
Neoplasm Recurrence, Local
Original
PGE2
Phenotypes
PLA2G4A
Polymerase chain reaction
Prostaglandin E2
Prostate cancer
Prostatic Neoplasms, Castration-Resistant - drug therapy
Protein folding
Receptors, Androgen - metabolism
Tumor cells
AA
PGE2
PLA2G4A
ferroptosis
ATF6α
CRPC
ISSN:0270-4137, 1097-0045, 1097-0045
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Shrnutí: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.
Bibliografie:Ru Zhao and Ye Lv contributed equally to this study.
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ISSN:0270-4137
1097-0045
1097-0045
DOI:10.1002/pros.24308