journal contribution posted on 2023-03-31, 03:06 authored by Makiko Hayashi, Ayumi Kuga, Mikiko Suzuki, Harit Panda, Hiroshi Kitamura, Hozumi Motohashi, Masayuki Yamamoto
Figure S1: Expression of Keap1 and Nqo1 in Keap1WT/WT, Keap1FB/FB and Keap1FA/FA mouse tissues; Figure S2: Analyses of tumor-bearing mouse cohorts; Figure S3: Origins of tumor cells in Kras::Keap1WT/WT, Kras::Keap1FB/FB and Kras::Keap1FA/FA lungs; Figure S4. Analyses of tumor-bearing Kras::Keap1FA/FA mouse cohorts that received Keap1FA/FA, Keap1WT/WT or Nrf2-/- bone marrows; Table S1: Primers and probes for qRT-PCR analyses; Table S2: Primers for analyses of recombination efficiency; Supplementary Materials and Methods (Establishment of mouse embryonic fibroblasts (MEFs), Validation of the recombination efficiency, Immunoblot analyses, Histology and Immunohistochemistry, Flow cytometry, and isolation of CD8+ T cells in tumor-bearing lungs)
Japan Agency for Medical and Development
Japan Society for the Promotion of Science
Mitsubishi Life Science Foundation
Takeda Science Foundation
Platform Project for Supporting in Drug Discovery and Life Science Research
Ministry of Education, Culture, Sports, Science and Technology
Princess Takamatsu Cancer Research Fund
ARTICLE ABSTRACTThe transcription factor Nrf2 activates transcription of cytoprotective genes during oxidative and electrophilic insults. Nrf2 activity is regulated by Keap1 in a stress-dependent manner in normal cells, and somatic loss-of-function mutations of Keap1 are known to induce constitutive Nrf2 activation, especially in lung adenocarcinomas, conferring survival and proliferative benefits to tumors. Therefore, several therapeutic strategies that aim to inhibit Nrf2 in tumors have been developed for the treatment of Nrf2-activated cancers. Here we addressed whether targeting Nrf2 activation in the microenvironment can suppress the progression of Nrf2-activated tumors. We combined two types of Keap1-flox mice expressing variable levels of Keap1 with a Kras-driven adenocarcinoma model to generate Keap1-deficient lung tumors surrounded by normal or Keap1-knockdown host cells. In this model system, activation of Nrf2 in the microenvironment prolonged the survival of Nrf2-activated tumor-bearing mice. The Nrf2-activated microenvironment suppressed tumor burden; in particular, preinvasive lesion formation was significantly suppressed. Notably, loss of Nrf2 in bone marrow–derived cells in Nrf2-activated host cells appeared to counteract the suppression of Nrf2-activated cancer progression. Thus, these results demonstrate that microenvironmental Nrf2 activation suppresses the progression of malignant Nrf2-activated tumors and that Nrf2 activation in immune cells at least partially contributes to these suppressive effects.
This study clarifies the importance of Nrf2 activation in the tumor microenvironment and in the host for the suppression of malignant Nrf2-activated cancers and proposes new cancer therapies utilizing inducers of Nrf2.