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

Toxicol Appl Pharmacol. 2020 Sep 01;402:115121. Epub 2020 Jul 01
Soma Saeidi 1 , Su-Jung Kim 2 , Hyeong-Jun Han 2 , Seong Hoon Kim 2 , Jie Zheng 2 , Han-Byoel Lee 3 , Wonshik Han 3 , Dong-Young Noh 3 , Hye-Kyung Na 4 , Young-Joon Surh 5
Soma Saeidi 1 , Su-Jung Kim 2 , Hyeong-Jun Han 2 , Seong Hoon Kim 2 , Jie Zheng 2 , Han-Byoel Lee 3 , Wonshik Han 3 , Dong-Young Noh 3 , Hye-Kyung Na 4 , Young-Joon Surh 5
+ et al

[No authors listed]

Author information
  • 1 Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine, Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.
  • 2 Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.
  • 3 Cancer Research Institute, Seoul National University, Seoul, South Korea; Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.
  • 4 Department of Food Science and Biotechnology, College of Knowledge-Based Services Engineering, Sungshin Women's University, Seoul, South Korea.
  • 5 Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine, Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea; Cancer Research Institute, Seoul National University, Seoul, South Korea. Electronic address: surh@snu.ac.kr.

摘要

Aberrant activation of H-Ras is often associated with tumor aggressiveness in breast cancer. Peptidyl-prolyl cis-trans 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.

KEYWORDS: Breast cancer, H-Ras, Nrf2, Pin1, Protein-protein interaction

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