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Supplementary Figure S1 from NRF2 Intensifies Host Defense Systems to Prevent Lung Carcinogenesis, but After Tumor Initiation Accelerates Malignant Cell Growth

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posted on 2023-03-30, 23:30 authored by Hironori Satoh, Takashi Moriguchi, Daisuke Saigusa, Liam Baird, Lei Yu, Hirofumi Rokutan, Keiko Igarashi, Masahito Ebina, Tatsuhiro Shibata, Masayuki Yamamoto

Ki67 immuno-staining and H.E staining in the Keap1-wt mice and Keap1-kd mice.

Funding

Ministry of Education, Culture, Sports, Science, and Technology and the Japan Society for Promotion of Science

Scientific Research on Priority Areas

Specially Promoted Research

Research Fellowships of Japan Society for the Promotion of Science for Young Scientists

MEXT/JSPS KAKENHI

AMED-CREST, AMED

P-DIRECT, AMED

Takeda Science Foundation

History

ARTICLE ABSTRACT

Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating antioxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2, cancer chemoprevention and cancer cell growth enhancement, can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice, which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd–derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis. Cancer Res; 76(10); 3088–96. ©2016 AACR.

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