Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis.

Authors:
Shin Hamada
Shin Hamada
Tohoku University Graduate School of Medicine
Sendai | Japan
Keiko Taguchi
Keiko Taguchi
Tohoku University Graduate School of Medicine
Sendai | Japan
Atsushi Masamune
Atsushi Masamune
Tohoku University Graduate School of Medicine
Sendai | Japan
Masayuki Yamamoto
Masayuki Yamamoto
Tohoku University Graduate School of Medicine
Sendai | Japan
Tooru Shimosegawa
Tooru Shimosegawa
Tohoku University Graduate School of Medicine
Japan

Carcinogenesis 2017 06;38(6):661-670

Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

The Keap1-Nrf2 system contributes to the maintenance of homeostasis by regulating oxidative stress responses in normal tissues and organs, and is exploited in various cancers for proliferation, survival and acquisition of therapy resistance. Pancreatic cancer remains one of the intractable cancers, despite the improved clinical outcomes of other types of cancer, due to its invasive and refractory nature to therapeutic intervention. The current study aimed to clarify the contribution of Nrf2 to pancreatic carcinogenesis using a pancreas-specific mutant K-ras and p53 (KPC) mouse model. Deletion of Nrf2 in KPC mice (KPCN) decreased the formation of precancerous lesions as well as the development of invasive pancreatic cancer. The pancreatic tumor-derived cancer cell lines from KPCN mouse showed decreased expression of glutathione S-transferases (GST), UDP glucuronosyltransferases (UGT) and ABC transporters. Along with these biochemical changes, cell lines from KPCN mice revealed increased sensitivity to oxidative stress and chemotherapeutic agent. The current study revealed that Nrf2 contributes to pancreatic carcinogenesis in a way distinct from the chemoresistance of lung and esophagus, and that Nrf2 could be a novel therapeutic target of pancreatic cancer.

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http://dx.doi.org/10.1093/carcin/bgx043DOI Listing

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June 2017
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