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H-Ras induces Nrf2-Pin1 interaction: Implications for breast cancer progression

Cited 3 time in Web of Science Cited 3 time in Scopus
Issue Date
2020-09
Citation
Toxicology and Applied Pharmacology, Vol.402, p. 115121
Keywords
H-RasPin1Nrf2Protein-protein interactionBreast cancer
Abstract
Aberrant activation of H-Ras is often associated with tumor aggressiveness in breast cancer. Peptidyl-prolyl cistrans isomerase NIMA-interacting 1 (Pin1) is a unique enzyme that interacts with phosphorylated serine or threonine of a target protein and isomerizes the adjacent proline residue. Pin1 is prevalently overexpressed in human cancers, and its overexpression correlates with poor prognosis. Nuclear factor E2-related factor 2 (Nrf2) is a master regulator of cellular redox homeostasis. The sustained activation/accumulation of Nrf2 has been observed in many different types of human malignancies, conferring an advantage for growth and survival of cancer cells. The activated form of H-Ras (GTP-H-Ras) is highly overexpressed in human breast cancer tissues. In our present study, silencing of H-Ras decreased the invasiveness of MDA-MB-231 human breast cancer cells and abrogated the interaction between Pin1 and Nrf2 in these cells. Pin1 knockdown blocked the accumulation of Nrf2, thereby suppressing proliferation and clonogenicity of MCF10A-Ras human mammary epithelial cells. We found that Pin1 binds to Nrf2 which stabilizes this transcription factor by hampering proteasomal degradation. In conclusion, H-Ras activation in cooperation with the Pin1-Nrf2 complex represents a novel mechanism underlying breast cancer progression and constitutive activation of Nrf2 and can be exploited as a therapeutic target.
ISSN
0041-008X
URI
https://hdl.handle.net/10371/172910
DOI
https://doi.org/10.1016/j.taap.2020.115121
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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