Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma

Shin Hamada, Tooru Shimosegawa, Keiko Taguchi, Tatsuhide Nabeshima, Masayuki Yamamoto, Atsushi Masamune

The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response, such as growth promotion and chemoresistance of cancer cells. Nrf2 is constitutively activated in most cancer cells. However, the activation of Nrf2 together with oncogenic mutations does not always result in cancer promotion. K-ras(LSL-G12D/+)::p53(LSL-R172H/+)::Pdx-1-Cre (KPC) mice are an established model of pancreatic cancer, which specifically express mutants of both K-ras and p53 in the pancreas by using Pdx-1-Cre. We here generated KC::Keap1(fl/fl) (KC::Keap1) and KPC::Keap1(fl/fl) (KPC::Keap1) mice in which Nrf2 is constitutively activated by Keap1 deletion. KC::Keap1 and KPC::Keap1 mice started to die or showed obvious weakness at approximately around 40 days after birth. Histological examination revealed that KC::Keap1 and KPC::Keap1 mice did not develop pancreatic cancer, but, instead, progressive atrophy of the pancreatic parenchyma. In these mice, amylase-positive acinar cells as well as insulin- and glucagon-positive islet cells were decreased and surrounded by fibrotic tissues. KC::Keap1 and KPC::Keap1 mice presented lower body weight and glucose levels than C::Keap1 mice, presumably resulting from pancreatic exocrine insufficiency. Histological changes were not obvious in C::Keap1 and PC::Keap1 mice. The presence of the p53 mutation did not affect the phenotypes in KC::Keap1 mice. Heterologous or homologous Nrf2 deletion (Nrf2(+/-) or Nrf2(-/-)) rescued the pancreatic phenotypes, weight loss and hypoglycemia in KC::Keap1 mice, suggesting that Nrf2 is a major downstream target of Keap1. In conclusion, simultaneous K-ras activation and Keap1 deletion caused progressive atrophy of the pancreatic parenchyma in mice.