Roles of JNK/Nrf2 Pathway on Hemin-Induced Heme Oxygenase-1 Activation in MCF-7 Human Breast Cancer Cells.

Hye-Yeon Jang,Kwang-Hyun Park,Jong-Suk Kim,Eun-Yong Chung,On-Yu Hong

doi:10.3390/medicina56060268

Abstract

Heme oxygenase-1 (HO-1) is highly induced in various human disease states, including cancer, indicating that HO-1 is an emerging target of cancer therapy. In this study, we investigated that the mechanisms of hemin-induced HO-1 expression and its signaling pathways in human breast cancer cell. We used MCF-7 cells, a human breast cancer cell line. Hemin increased HO-1 expression in MCF-7 cells in a dose- and time-dependent manner. Hemin enhanced HO-1 expression through the activation of c-Jun N-terminal kinases (JNK) signaling pathway. Hemin also induced activation of Nrf2, a major transcription factor of HO-1 expression. These responses in MCF-7 cells were completely blocked by pretreatment with brazilin, a HO-1 regulator. These results indicated that brazilin inhibits hemin-induced HO-1 expressions through inactivation of JNK/Nrf2 in MCF-7 cells. Thus, our findings suggest that HO-1 is an important anticancer-target of brazilin in human breast cancer.

Highlights

Heme oxygenase-1 (HO-1) was identified by Maines [1], as a liver microsomal protein with degradation activity of heme to bilirubin
Treatment of Michigan Cancer Foundation (MCF)-7 cells with indicated dosage of brazilin and hemin shown no significant change in cell viability (Figure 2A,B)
This study provides evidence that brazilin, a major component of Caesalpinia sappan, blocks hemin-induced heme oxygenase (HOs)-1 expression in MCF-7 cells and Jun N-terminal kinases (JNK)/Nrf2-mediated HO-1 expression

Summary

Introduction

Heme oxygenase-1 (HO-1) was identified by Maines [1], as a liver microsomal protein with degradation activity of heme to bilirubin. HO-1 catalyzes the degradation of heme to form the open-chain tetrapyrrole biliverdin-Ixα, carbon monoxide (CO), and free iron, which play crucial roles in the adaptation to defense against oxidative stress and cellular stress [2,3]. HO-1 is induced in cells by cellular stress including oxidants [4], hypoxia condition [5], cytokine [6,7], and ultraviolet light irradiation [5,8]. These findings suggest that HO-1 has cytoprotective actions. It is known that expression of high level of HO-1 occurs in various tumors including in renal cancer [15], acute

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Conclusion