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Heregulin-β1 Activates NF-E2-related Factor 2 and Induces Manganese Superoxide Dismutase Expression in Human Breast Cancer Cells via Protein Kinase B and Extracellular Signal-regulated Protein Kinase Signaling Pathways

Journal of Cancer Prevention 2021년 26권 1호 p.54 ~ 63
박지영, Saeidi Soma, 김은희, 김도희, 나혜경, 금주섭, 서영준,
소속 상세정보
박지영 ( Park Ji-Young ) - Seoul National University College of Pharmacy
 ( Saeidi Soma ) - Seoul National University College of Pharmacy
김은희 ( Kim Eun-Hee ) - CHA University College of Pharmacy
김도희 ( Kim Do-Hee ) - Kyonggi University College of Convergence and Integrated Science Department of Chemistry
나혜경 ( Na Hye-Kyung ) - Sungshin Women’s University College of Knowledge-based Services Engineering Department of Food Science and Biotechnology
금주섭 ( Keum Joo-Seob ) - Sungkyunkwan University School of Medicine Kangbuk Samsung Hospital Department of Pathology
서영준 ( Surh Young-Joon ) - Seoul National University College of Pharmacy

Abstract


Heregulin-β1, a ligand of ErbB-2 and ErbB-3/4 receptors, has been reported to potentiate oncogenicity and metastatic potential of breast cancer cells. In the present work, treatment of human mammary cancer (MCF-7) cells with heregulin-β1 resulted in enhanced cell migration and expression of manganese superoxide dismutase (MnSOD) and its mRNA transcript. Silencing of Mn-SOD abrogated clonogenicity and migrative ability of MCF-7 cells. Heregulin-β1 treatment also increased nuclear translocation, antioxidant response element binding and transcriptional activity of NF-E2-related factor 2 (Nrf2). A dominant-negative mutant of Nrf2 abrogated heregulin-β1-induced MnSOD expression. Treatment with heregulin-β1 caused activation of protein kinase B (Akt) and extracellular signal-regulated protein kinase (ERK). The pharmacological inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase 1/2, which are upstream of Akt and ERK, respectively, attenuated heregulin-β1-induced Mn-SOD expression and nuclear localization of Nrf2. In conclusion, heregulin-1 induces upregulation of MnSOD and activation of Nrf2 via the Akt and ERK signaling in MCF-7 cells, which may confer metastatic potential and invasiveness of these cells.

키워드

Breast cancer; Heregulin-β1; Manganese superoxide dismutase; NF-E2-related factor 2

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