Potential Antitumor Effects of 6-Gingerol in p53-Dependent Mitochondrial Apoptosis and Inhibition of Tumor Sphere Formation in Breast Cancer Cells.

Nipin Sp,Jin-Moo Lee,Se Won Bae,Dong Young Kang,Kyoung-Jin Jang

doi:10.3390/ijms22094660

Abstract

Hormone-specific anticancer drugs for breast cancer treatment can cause serious side effects. Thus, treatment with natural compounds has been considered a better approach as this minimizes side effects and has multiple targets. 6-Gingerol is an active polyphenol in ginger with various modalities, including anticancer activity, although its mechanism of action remains unknown. Increases in the level of reactive oxygen species (ROS) can lead to DNA damage and the induction of DNA damage response (DDR) mechanism, leading to cell cycle arrest apoptosis and tumorsphere suppression. Epidermal growth factor receptor (EGFR) promotes tumor growth by stimulating signaling of downstream targets that in turn activates tumor protein 53 (p53) to promote apoptosis. Here we assessed the effect of 6-gingerol treatment on MDA-MB-231 and MCF-7 breast cancer cell lines. 6-Gingerol induced cellular and mitochondrial ROS that elevated DDR through ataxia-telangiectasia mutated and p53 activation. 6-Gingerol also induced G0/G1 cell cycle arrest and mitochondrial apoptosis by mediating the BAX/BCL-2 ratio and release of cytochrome c. It also exhibited a suppression ability of tumorsphere formation in breast cancer cells. EGFR/Src/STAT3 signaling was also determined to be responsible for p53 activation and that 6-gingerol induced p53-dependent intrinsic apoptosis in breast cancer cells. Therefore, 6-gingerol may be used as a candidate drug against hormone-dependent breast cancer cells.

Highlights

Breast cancer has one of the highest mortality rates of cancer among women, and it has been identified as the fifth most common cancer type in Korea, accounting for more than 20% of cancers [1]
Our results suggested an arrest in the G0/G1 phase of the cell cycle by 6-gingerol, which indicates that DNA damage triggers to DNA damage response (DDR) which upon failure culminates in prolonged cell cycle arrest in breast cancer cells (Figure 3B)
Our results suggested the induction of DDR by 6-gingerol in breast cancer cells as it activates ataxia-telangiectasia mutated (ATM)/p53/CHK/BRCA1 signaling which suggested that ATM may play a key role in 6-gingerol-induced DDR mechanism in MDA-MB-231 cells

Summary

Introduction

Breast cancer has one of the highest mortality rates of cancer among women, and it has been identified as the fifth most common cancer type in Korea, accounting for more than 20% of cancers [1]. The incidence of breast cancer has increased significantly since 1970, which can be linked to modern living, as environmental factors are known to play a key role in tumorigenesis [2]. Estrogen and progesterone receptors (ER and PR) and human epidermal growth factor 2 (HER2) statuses play a vital role in breast cancer development [4]. Hormone receptor status is highly useful in breast cancer treatment; chemotherapy is limited by possible adverse effects. Natural compounds for anticancer treatment can be effectively assessed for activity using hormone-specific breast cancer cells such as MCF-7 (ERα positive) or MDA-MB-231 (triple negative) [5]. A number of natural compounds have been found to have anticancer properties against different types of cancer without significant side effects [6,7,8]. The exact mechanism of cell death by 6-gingerol in breast cancer is yet to be discovered

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