Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling

被引：124

作者：

Zhang, Weifan ^{[1
]}

Gong, Mengyuan ^{[1
]}

Zhang, Wunai ^{[1
]}

Mo, Jiantao ^{[1
]}

Zhang, Simei ^{[1
]}

Zhu, Zeen ^{[1
]}

Wang, Xueni ^{[1
]}

Zhang, Bo ^{[1
]}

Qian, Weikun ^{[1
]}

Wu, Zheng ^{[1
]}

Ma, Qingyong ^{[1
]}

Wang, Zheng ^{[1
,2
]}

机构：

[1] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Xian 710061, Shaanxi, Peoples R China

[2] Xi An Jiao Tong Univ, Pancreas Ctr, Xian 710061, Shaanxi, Peoples R China

来源：

CELL DEATH & DISEASE | 2022年 / 13卷 / 07期

基金：

中国国家自然科学基金;

关键词：

STRESS;

D O I：

10.1038/s41419-022-05082-3

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Ferroptosis is a new form of regulated cell death that is mediated by intracellular iron and ester oxygenase, and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols. Although thiostrepton (TST) has been reported to exert antitumor effects, its role in pancreatic cancer and the underlying mechanisms remain unclear. In this study, we found that TST reduced the viability and clonogenesis of pancreatic cancer cell lines, along with intracellular iron overload, increasing reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) overexpression, and glutathione peroxidase (GSH-PX) depletion. Mechanistically, chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays were used to confirm that signal transducer and activator of transcription 3 (STAT3) binds to the GPX4 promoter region and promotes its transcription, whereas TST blocked GPX4 expression by regulating STAT3. Finally, in vivo experiments revealed that TST inhibited the growth of subcutaneously transplanted tumours and had considerable biosafety. In conclusion, our study identified the mechanism by which TST-induced ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling.

引用

页数：12

共 37 条

[1] Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice [J].

Angeli, Jose Pedro Friedmann ;

Schneider, Manuela ;

Proneth, Bettina ;

Tyurina, Yulia Y. ;

Tyurin, Vladimir A. ;

Hammond, Victoria J. ;

Herbach, Nadja ;

Aichler, Michaela ;

Walch, Axel ;

Eggenhofer, Elke ;

Basavarajappa, Devaraj ;

Radmark, Olof ;

Kobayashi, Sho ;

Seibt, Tobias ;

Beck, Heike ;

Neff, Frauke ;

Esposito, Irene ;

Wanke, Ruediger ;

Foerster, Heidi ;

Yefremova, Olena ;

Heinrichmeyer, Marc ;

Bornkamm, Georg W. ;

Geissler, Edward K. ;

Thomas, Stephen B. ;

Stockwell, Brent R. ;

O'Donnell, Valerie B. ;

Kagan, Valerian E. ;

Schick, Joel A. ;

Conrad, Marcus .

NATURE CELL BIOLOGY, 2014, 16 (12) :1180-U120

[2] The bacterial thiopeptide thiostrepton. An update of its mode of action, pharmacological properties and applications [J].

Bailly, Christian .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2022, 914

[3] Broadening the Impact of Immunotherapy to Pancreatic Cancer: Challenges and Opportunities [J].

Balachandran, Vinod P. ;

Beatty, Gregory L. ;

Dougan, Stephanie K. .

GASTROENTEROLOGY, 2019, 156 (07) :2056-2072

[4] Gemcitabine resistance in pancreatic ductal adenocarcinoma [J].

Binenbaum, Yoav ;

Na'ara, Shorook ;

Gil, Ziv .

DRUG RESISTANCE UPDATES, 2015, 23 :55-68

[5] Targeting ferroptosis in pancreatic cancer: a double-edged sword [J].

Chen, Xin ;

Kang, Rui ;

Kroemer, Guido ;

Tang, Daolin .

TRENDS IN CANCER, 2021, 7 (10) :891-901

[6] Targeting Ferroptosis: New Hope for As-Yet-Incurable Diseases [J].

Conrad, Marcus ;

Lorenz, Svenja M. ;

Proneth, Bettina .

TRENDS IN MOLECULAR MEDICINE, 2021, 27 (02) :113-122

[7] Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein [J].

Dai, Enyong ;

Han, Leng ;

Liu, Jiao ;

Xie, Yangchun ;

Kroemer, Guido ;

Klionsky, Daniel J. ;

Zeh, Herbert J. ;

Kang, Rui ;

Wang, Jing ;

Tang, Daolin .

AUTOPHAGY, 2020, 16 (11) :2069-2083

[8]

DONOVICK R, 1955, Antibiot Annu, V3, P554

[9] FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation [J].

Gaschler, Michael M. ;

Andia, Alexander A. ;

Liu, Hengrui ;

Csuka, Joleen M. ;

Hurlocker, Brisa ;

Vaiana, Christopher A. ;

Heindel, Daniel W. ;

Zuckerman, Dylan S. ;

Bos, Pieter H. ;

Reznik, Eduard ;

Ye, Ling F. ;

Tyurina, Yulia Y. ;

Lin, Annie J. ;

Shchepinov, Mikhail S. ;

Chan, Amy Y. ;

Peguero-Pereira, Eveliz ;

Fomich, Maksim A. ;

Daniels, Jacob. D. ;

Bekish, Andrei V. ;

Shmanai, Vadim V. ;

Kagan, Valerian E. ;

Mahal, Lara K. ;

Woerpel, K. A. ;

Stockwell, Brent R. .

NATURE CHEMICAL BIOLOGY, 2018, 14 (05) :507-+

[10] Proteomic analysis reveals a role for PAX8 in peritoneal colonization of high grade serous ovarian cancer that can be targeted with micelle encapsulated thiostrepton [J].

Hardy, Laura R. ;

Pergande, Melissa R. ;

Esparza, Karina ;

Heath, Kimberly N. ;

Onyuksel, Hayat ;

Cologna, Stephanie M. ;

Burdette, Joanna E. .

ONCOGENE, 2019, 38 (32) :6003-6016

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