Genetic alterations of Keap1 confers chemotherapeutic resistance through functional activation of Nrf2 and Notch pathway in head and neck squamous cell carcinoma
Keap1 mutations regulate Nrf2 activity and lead to chemoresistance in cancers. Yet the underlying molecular mechanisms of chemoresistance are poorly explored. By focusing and genotyping head and neck squamous cell carcinoma (HNSCC) that had available pathologic and clinical data, we provide evidence...
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Published in | Cell death & disease Vol. 13; no. 8; p. 696 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
09.08.2022
Springer Nature B.V Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | Keap1
mutations regulate
Nrf2
activity and lead to chemoresistance in cancers. Yet the underlying molecular mechanisms of chemoresistance are poorly explored. By focusing and genotyping head and neck squamous cell carcinoma (HNSCC) that had available pathologic and clinical data, we provide evidence that
Keap1
displays frequent alterations (17%) in HNSCC. Functional loss of
Keap1
results in significant activation of
Nrf2
and promotes cancer cell growth, proliferation, and elevated cancer stem cell (CSCs) self-renewal efficiency and resistance to oxidative stress. Furthermore, decreased
Keap1
activity in these cells increased nuclear accumulation of
Nrf2
and activation of the Notch pathway, causing enhanced transcriptional alterations of antioxidants, xenobiotic metabolism enzymes, and resistance to chemotherapeutic treatment. Limiting the
Nrf2
activity by either
Keap1
complementation or by
Nrf2
silencing increased the sensitivity to chemotherapy in
Keap1
-mutated cells and repressed the CSC self-renewal activity. Our findings suggest that
Keap1
mutations define a distinct disease phenotype and the
Keap1-Nrf2
pathway is one of the leading molecular mechanisms for clinical chemotherapeutic resistance. Targeting this pathway may provide a potential and attractive personalized treatment strategy for overcoming chemotherapeutic resistance conferred by
Keap1
mutations. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2041-4889 2041-4889 |
DOI: | 10.1038/s41419-022-05126-8 |