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Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis
Shin Hamada1, Keiko Taguchi2, Atsushi Masamune1
1Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
Carcinogenesis
|December 15, 2017
Summary
The Keap1-Nrf2 system drives pancreatic cancer progression. Inhibiting Nrf2 in pancreatic cancer models reduced tumor development and increased sensitivity to chemotherapy, suggesting Nrf2 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The Keap1-Nrf2 pathway regulates cellular responses to oxidative stress and is implicated in cancer proliferation and therapy resistance.
- Pancreatic cancer is highly invasive and resistant to treatment, necessitating novel therapeutic strategies.
- The role of Nrf2 in pancreatic carcinogenesis is not fully understood.
Purpose of the Study:
- To investigate the contribution of Nrf2 to pancreatic cancer development using a KPC mouse model.
- To assess the impact of Nrf2 deletion on precancerous lesions and invasive tumor growth.
- To evaluate the chemosensitivity and oxidative stress response of Nrf2-deficient pancreatic cancer cells.
Main Methods:
- Utilized a pancreas-specific mutant K-ras and p53 (KPC) mouse model.
- Generated Nrf2-deleted KPC mice (KPCN) to study Nrf2's role.
- Analyzed tumor-derived cell lines for gene expression (GST, UGT, ABC transporters) and sensitivity to oxidative stress and chemotherapeutic agents.
Main Results:
- Nrf2 deletion in KPC mice significantly reduced precancerous lesions and invasive pancreatic cancer.
- Pancreatic cancer cell lines from KPCN mice exhibited decreased expression of GST, UGT, and ABC transporters.
- Nrf2-deficient cells showed increased sensitivity to oxidative stress and chemotherapeutic agents compared to controls.
Conclusions:
- Nrf2 plays a crucial role in pancreatic carcinogenesis, distinct from its role in lung and esophageal cancers.
- Nrf2 promotes pancreatic tumor development and chemoresistance.
- Targeting Nrf2 represents a potential novel therapeutic strategy for pancreatic cancer.
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