Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling.
Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling.
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DOI：
10.1186/s11658-021-00271-y
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发表时间：
2021-06-07
影响因子：
8.3
通讯作者：
Yu R
中科院分区：
文献类型：
--
作者：
Fu D;Wang C;Yu L;Yu R
顺铂（DDP）耐药是影响进展期胃癌（GC）化疗成功的常见问题。在这里，我们试图调查的功能，激活转录因子3（ATF 3）的GC化疗耐药。在GC细胞系（MNK 45、SGC 7901和BGC 823）和顺铂（DDP）抗性细胞（SGC 7901/DDP和BGC 823/DDP）中测定ATF 3的表达。应用生物信息学方法分析ATF 3在胃癌中的表达及其与预后的关系。评价顺铂耐药性。在ATF 3转染细胞后检测到铁凋亡。并探讨了其分子机理。ATF 3在胃癌细胞和胃癌组织中的转录水平均降低。Kaplan-Meier回归分析显示ATF 3表达与胃癌患者的总生存期呈正相关。特别是，与其亲本细胞相比，在顺铂耐药的SGC 7901/DDP和BGC 823/DDP中观察到较低水平的ATF 3。值得注意的是，ATF 3升高使顺铂耐药细胞对顺铂敏感。与亲本细胞相比，SGC 7901/DDP和BGC 823/DDP细胞表现出较低的ROS、MDA和脂质过氧化水平以及较高的细胞内GSH水平，从而明显降低了铁凋亡。而ATF 3可使SGC 7901/DDP和BGC 823/DDP细胞的铁凋亡增加。有趣的是，ATF 3过表达与铁凋亡激活剂erastin或RSL 3治疗一起进一步增强了铁凋亡和顺铂耐药性;然而，铁凋亡抑制剂livestatin-1逆转了ATF 3在铁凋亡和顺铂耐药性中的功能。此外，顺铂耐药细胞表现出更强的激活Nrf 2/Keap 1/xCT信号相对于亲本细胞，这是抑制ATF 3上调。重要的是，恢复Nrf 2信号转导逆转了ATF 3介导的铁凋亡和顺铂耐药。ATF 3可以通过阻断Nrf 2/Keap 1/xCT信号转导诱导铁凋亡来使GC细胞对顺铂敏感，支持克服GC中化学抗性的有希望的治疗方法。
Currently, resistance against cisplatin (DDP) is a frequent problem for the success of advanced gastric carcinoma (GC) chemotherapy. Here, we sought to investigate the function of activating transcription factor 3 (ATF3) n GC chemoresistance. Expression of ATF3 was determined in GC cell lines (MNK45, SGC7901, and BGC823) and cisplatin (DDP)-resistant cells (SGC7901/DDP and BGC823/DDP). Biological informatics was performed to analyze ATF3 expression and prognosis in GC patients. Cisplatin resistance was evaluated. Ferroptosis was detected after ATF3 transfection of cells. The underlying molecular mechanism was also investigated. Transcripts of ATF3 were decreased in GC cells and GC tissues. Kaplan–Meier plotter analysis revealed that ATF3 expression was positively related to the overall survival of GC patients. In particular, lower levels of ATF3 were observed in cisplatin-resistant SGC7901/DDP and BGC823/DDP relative to their parental cells. Notably, ATF3 elevation sensitized cisplatin-resistant cells to cisplatin. Mechanically, compared with parental cells, SGC7901/DDP and BGC823/DDP cells exhibited lower ferroptosis evident by lower ROS, MDA and lipid peroxidation and higher intracellular GSH levels. However, ATF3 elevated ferroptosis in SGC7901/DDP and BGC823/DDP cells. Intriguingly, ATF3 overexpression together with ferroptosis activator erastin or RSL3 treatment further enhanced ferroptosis and cisplatin resistance; however, the ferroptosis suppressor liproxstatin-1 reversed the function of ATF3 in ferroptosis and cisplatin resistance. Additionally, cisplatin-resistant cells exhibited stronger activation of Nrf2/Keap1/xCT signaling relative to parental cells, which was restrained by ATF3 up-regulation. Importantly, restoring Nrf2 signaling overturned ATF3-mediated ferroptosis and cisplatin resistance. ATF3 may sensitize GC cells to cisplatin by induction of ferroptosis via blocking Nrf2/Keap1/xCT signaling, supporting a promising therapeutic approach for overcoming chemoresistance in GC.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
ATF3通过上调CYR61表达抑制肝癌细胞的肿瘤发生和进展
DOI：
10.1186/s13046-018-0919-8
发表时间：
2018-10-30
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Chen C;Ge C;Liu Z;Li L;Zhao F;Tian H;Chen T;Li H;Yao M;Li J
通讯作者：
Li J
影响因子：
4.4
作者：
Venerito, Marino;Vasapolli, Riccardo;Malfertheiner, Peter
通讯作者：
Malfertheiner, Peter
青藤碱通过 Nrf2-Keap1 和自噬减轻脓毒症相关肺损伤
影响因子：
3.3
作者：
Wang, Wanqiu;Yang, Xiaoting;Huang, Fengjie
通讯作者：
Huang, Fengjie
影响因子：
4.8
作者：
Bar, Jair;Hasim, Mohamed S.;Baghai, Tabassom;Niknejad, Nima;Perkins, Theodore J.;Stewart, David J.;Sekhon, Harmanjatinder S.;Villeneuve, Patrick J.;Dimitroulakos, Jim
通讯作者：
Dimitroulakos, Jim