ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis.
ATF6α promotes prostate cancer progression by enhancing PLA2G4A-mediated arachidonic acid metabolism and protecting tumor cells against ferroptosis.
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ATF6α 通过增强 PLA2G4A 介导的花生四烯酸代谢并保护肿瘤细胞免受铁死亡来促进前列腺癌进展
DOI：
10.1002/pros.24308
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发表时间：
2022-04
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影响因子：
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中科院分区：
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尽管雄激素受体（AR）靶向治疗取得了临床成功，但前列腺癌（PCa）不可避免地进展为去势抵抗性前列腺癌（CRPC）。转录因子6 α（ATF 6 α）是未折叠蛋白反应（UPR）的效应子，调节细胞对内质网（ER）应激的反应，与肿瘤的发生、转移和复发有关。然而，ATF 6 α在CRPC中的作用仍不清楚。通过3-（4，5-二甲基噻唑-2-基）−5-（3-羧基-甲氧基苯基）−2-（4-磺基苯基）− 2 H-四唑内盐（MTS）、5-溴-2-脱氧尿苷（BrdU）掺入分析和细胞死亡试验，评价ATF 6 α对PCa细胞中CRPC样表型的影响。在机制上，利用生物信息学分析来评估PLA 2G 4A作为ATF 6 α靶点的潜力。此外，通过Western blot分析、真实的-时间聚合酶链反应、染色质免疫沉淀、花生四烯酸（AA）和前列腺素E2（PGE 2）测定来鉴定ATF 6 α对PLA 2G 4A的调节作用。在这项研究中，我们发现ATF 6 α表达的增加对雄激素剥夺的反应产生了具有CRPC样表型的PCa细胞。高水平表达ATF 6 α的PCa细胞对铁凋亡具有抗性，因此，遗传和药理学抑制ATF 6 α可促进肿瘤细胞的铁凋亡死亡并延缓PCa进展。分子分析将ATF 6 α对铁凋亡的调节与PLA 2G 4A介导的AA释放以及导致的PGE 2产生增加联系起来，后者作为抗铁凋亡因子。这项研究将ATF 6 α定义为一种新的抗铁凋亡调节剂，可加剧PCa进展。此外，我们的数据确立了ATF 6 α-PLA 2G 4A信号传导是PCa的重要病理通路，靶向该通路可能是一种新的治疗策略。
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. 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. 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. 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.
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影响因子：
11.2
作者：
Karuppagounder SS;Alin L;Chen Y;Brand D;Bourassa MW;Dietrich K;Wilkinson CM;Nadeau CA;Kumar A;Perry S;Pinto JT;Darley-Usmar V;Sanchez S;Milne GL;Pratico D;Holman TR;Carmichael ST;Coppola G;Colbourne F;Ratan RR
通讯作者：
Ratan RR
影响因子：
4.8
作者：
Pullikotil, P;Vincent, M;Seidah, NG
通讯作者：
Seidah, NG
影响因子：
11.1
作者：
Sheng X;Arnoldussen YJ;Storm M;Tesikova M;Nenseth HZ;Zhao S;Fazli L;Rennie P;Risberg B;Wæhre H;Danielsen H;Mills IG;Jin Y;Hotamisligil G;Saatcioglu F
通讯作者：
Saatcioglu F
影响因子：
5.3
作者：
Higa, Arisa;Taouji, Said;Chevet, Eric
通讯作者：
Chevet, Eric
影响因子：
4.6
作者：
Lu, Jinsen;Yang, Jiazhao;Fang, Shiyuan
通讯作者：
Fang, Shiyuan