Activation of Nrf2 by Sulforaphane Inhibits High Glucose-Induced Progression of Pancreatic Cancer via AMPK Dependent Signaling

被引：59

作者：

Chen, Xin ^{[1
]}

Jiang, Zhengdong ^{[1
]}

Zhou, Cancan ^{[1
]}

Chen, Ke ^{[1
]}

Li, Xuqi ^{[2
]}

Wang, Zheng ^{[1
]}

Wu, Zheng ^{[1
]}

Ma, Jiguang ^{[3
]}

Ma, Qingyong ^{[1
]}

Duan, Wanxing ^{[1
]}

机构：

[1] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, 277 West Yanta Rd, Xian 710061, Shaanxi, Peoples R China

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

[3] Xi An Jiao Tong Univ, Affiliated Hosp 1, Dept Anesthesiol, Xian, Shaanxi, Peoples R China

来源：

CELLULAR PHYSIOLOGY AND BIOCHEMISTRY | 2018年 / 50卷 / 03期

关键词：

Sulforaphane; High glucose; Pancreatic cancer; Nrf2-AMPK signaling; ANTIDIABETIC MEDICATIONS; KAPPA-B; CELLS; APOPTOSIS; RISK; PREVENTION; PROTECTS; INVASION; TARGET; MICE;

D O I：

10.1159/000494547

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Background/Aims: Sulforaphane (SFN) is known for its potent bioactive properties, such as anti-inflammatory and anti-tumor effects. However, its anti-tumor effect on pancreatic cancer is still poorly understood. In the present study, we explored the therapeutic potential of SFN for pancreatic cancer and disclosed the underlying mechanism. Methods: Panc-1 and MiaPaca-2 cell lines were used in vitro. The biological function of SFN in pancreatic cancer was measured using EdU staining, colony formation, apoptosis, migration and invasion assays. Reactive oxygen species (ROS) production was measured using 2'-7'-Dichlorofluorescein diacetate (DCF-DA) fluorometric analysis. Western blotting and immunofluorescence were used to measure the protein levels of p-AMPK and epithelial-mesenchymal transition (EMT) pathway-related proteins, and cellular translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Nude mice and transgenic pancreatic cancer mouse model were used to measure the therapeutic potential of SFN on pancreatic cancer. Results: SFN can inhibit pancreatic cancer cell growth, promote apoptosis, curb colony formation and temper the migratory and invasion ability of pancreatic cancer cells. Mechanistically, excessive ROS production induced by SFN activated AMPK signaling and promoted the translocation of Nrf2, resulting in cell viability inhibition of pancreatic cancer. Pretreatment with compound C, a small molecular inhibitor of AMPK signaling, reversed the subcellular translocation of Nrf2 and rescued cell invasion ability. With nude mice and pancreatic cancer transgenic mouse, we identified SFN could inhibit tumor progression, with smaller tumor size and slower tumor progression in SFN treatment group. Conclusion: Our study not only elucidates the mechanism of SFN-induced inhibition of pancreatic cancer in both normal and high glucose condition, but also testifies the dual-role of ROS in pancreatic cancer progression. Collectively, our research suggests that SFN may serve as a potential therapeutic choice for pancreatic cancer. (C) 2018 The Author(s) Published by S. Karger AG, Basel

引用

页码：1201 / 1215

页数：15

共 39 条

[1]

Atwell Lauren L, 2015, Curr Pharmacol Rep, V1, P102

[2] Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane [J].

Bauman, Julie E. ;

Zang, Yan ;

Sen, Malabika ;

Li, Changyou ;

Wang, Lin ;

Egner, Patricia A. ;

Fahey, Jed W. ;

Normolle, Daniel P. ;

Grandis, Jennifer R. ;

Kensler, Thomas W. ;

Johnson, Daniel E. .

CANCER PREVENTION RESEARCH, 2016, 9 (07) :547-557

[3] Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium [J].

Bosetti, C. ;

Rosato, V. ;

Li, D. ;

Silverman, D. ;

Petersen, G. M. ;

Bracci, P. M. ;

Neale, R. E. ;

Muscat, J. ;

Anderson, K. ;

Gallinger, S. ;

Olson, S. H. ;

Miller, A. B. ;

Bueno-de-Mesquita, H. Bas ;

Scelo, G. ;

Janout, V. ;

Holcatova, I. ;

Lagiou, P. ;

Serraino, D. ;

Lucenteforte, E. ;

Fabianova, E. ;

Ghadirian, P. ;

Baghurst, P. A. ;

Zatonski, W. ;

Foretova, L. ;

Fontham, E. ;

Bamlet, W. R. ;

Holly, E. A. ;

Negri, E. ;

Hassan, M. ;

Prizment, A. ;

Cotterchio, M. ;

Cleary, S. ;

Kurtz, R. C. ;

Maisonneuve, P. ;

Trichopoulos, D. ;

Polesel, J. ;

Duell, E. J. ;

Boffetta, P. ;

La Vecchia, C. .

ANNALS OF ONCOLOGY, 2014, 25 (10) :2065-2072

[4] Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer [J].

Chen, Ke ;

Qian, Weikun ;

Jiang, Zhengdong ;

Cheng, Liang ;

Li, Jie ;

Sun, Liankang ;

Zhou, Cancan ;

Gao, Luping ;

Lei, Meng ;

Yan, Bin ;

Cao, Junyu ;

Duan, Wanxing ;

Ma, Qingyong .

MOLECULAR CANCER, 2017, 16

[5] Dietary broccoli protects against fatty liver development but not against progression of liver cancer in mice pretreated with diethylnitrosamine [J].

Chen, Yung-Ju ;

Myracle, Angela D. ;

Wallig, Matthew A. ;

Jeffery, Elizabeth H. .

JOURNAL OF FUNCTIONAL FOODS, 2016, 24 :57-62

[6] Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver [J].

Costa-Silva, Bruno ;

Aiello, Nicole M. ;

Ocean, Allyson J. ;

Singh, Swarnima ;

Zhang, Haiying ;

Thakur, Basant Kumar ;

Becker, Annette ;

Hoshino, Ayuko ;

Mark, Milica Tesic ;

Molina, Henrik ;

Xiang, Jenny ;

Zhang, Tuo ;

Theilen, Till-Martin ;

Garcia-Santos, Guillermo ;

Williams, Caitlin ;

Ararso, Yonathan ;

Huang, Yujie ;

Rodrigues, Goncalo ;

Shen, Tang-Long ;

Labori, Knut Jorgen ;

Lothe, Inger Marie Bowitz ;

Kure, Elm H. ;

Hernandez, Jonathan ;

Doussot, Alexandre ;

Ebbesen, Saya H. ;

Grandgenett, Paul M. ;

Hollingsworth, Michael A. ;

Jain, Maneesh ;

Mallya, Kavita ;

Batra, Surinder K. ;

Jarnagin, William R. ;

Schwartz, Robert E. ;

Matei, Irina ;

Peinado, Hector ;

Stanger, Ben Z. ;

Bromberg, Jacqueline ;

Lyden, David .

NATURE CELL BIOLOGY, 2015, 17 (06) :816-+

[7] KEAP1 and done? Targeting the NRF2 pathway with sulforaphane [J].

Dinkova-Kostova, Albena T. ;

Fahey, Jed W. ;

Kostov, Rumen V. ;

Kensler, Thomas W. .

TRENDS IN FOOD SCIENCE & TECHNOLOGY, 2017, 69 :257-269

[8] Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression [J].

Duan, Wanxing ;

Chen, Ke ;

Jiang, Zhengdong ;

Chen, Xin ;

Sun, Liankang ;

Li, Jiahui ;

Lei, Jianjun ;

Xu, Qinhong ;

Ma, Jiguang ;

Li, Xuqi ;

Han, Liang ;

Wang, Zheng ;

Wu, Zheng ;

Wang, Fengfei ;

Wu, Erxi ;

Ma, Qingyong ;

Ma, Zhenhua .

CANCER LETTERS, 2017, 385 :225-233

[9] Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors [J].

Fahey, JW ;

Haristoy, X ;

Dolan, PM ;

Kensler, TW ;

Scholtus, I ;

Stephenson, KK ;

Talalay, P ;

Lozniewski, A .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (11) :7610-7615

[10] Nuclear factor κB is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms [J].

Heiss, E ;

Herhaus, C ;

Klimo, K ;

Bartsch, H ;

Gerhäuser, C .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (34) :32008-32015

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