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Published on: June 7, 2019
Zerumbone Induced ROS-Mediated Autophagic Cell Death in Human Melanoma Cells: An In Vitro and In Vivo Study
Siang-Jyun Chen1, You-Cheng Hseu2,3,4,5, Yan-Ming Zhang2
1Institute of Nutrition, College of Health Care, China Medical University, Taichung, Taiwan.
Abstract:
Zerumbone (Zer), a natural sesquiterpene of Zingiber zerumbet, exerts apoptosis in human melanoma cells. We evaluated the anticancer efficacies and the underlying molecular mechanisms of Zer through autophagic cell death in both in vitro melanoma (A375 and/or A2058) cells and in vivo xenografted athymic nude mice. We found that Zer inhibited cell growth and EGFR/BRAF expression in A375 and A2058 cells. Additionally, Zer-induced autophagy was apparent from enhanced LC3-II accumulation, p62 expression, ATG4B reduction, Beclin-1/Bcl-2 ratio, AKT/mTOR suppression, and AVO production in A375 and A2058 cells. Surprisingly, Zer-triggered cell death was prevented by autophagic inhibitors 3-MA and CQ, suggesting the contribution of autophagy as a death mechanism. TEM data displayed that Zer provoked autophagosome generation in A375 and A2058 cells. However, obstruction of autophagy by 3-MA or CQ, and LC3 silencing curbed Zer-incited apoptosis in A375 cells, which suggests autophagy induction enhanced apoptosis in Zer-treated A375 cells. Interestingly, reduction of apoptosis by caspase blocker Z-VAD-FMK enhanced Zer-provoked autophagy in A375 cells, indicating induction of apoptosis inhibited autophagy in Zer-treated A375 cells. Moreover, Zer instigated intracellular ROS generation, whereas antioxidant NAC or Mito-Tempo reversed autophagic or apoptotic cell death in A375 and/or A2058 cells. In vivo results displayed that Zer significantly inhibited tumor development in A375 and A2058-xenografted athymic nude mice. Our findings implied that Zerumbone is a potent antitumor agent that triggered ROS-mediated autophagic cell death in human melanoma cells.
Insights
Zerumbone, a natural compound, effectively combats melanoma by inducing cell death through autophagy and apoptosis. This compound shows promise as an anticancer agent, inhibiting tumor growth in both cell cultures and animal models.
Area of Science:
- Natural Products Chemistry
- Cancer Biology
- Cellular Biology
Background:
- Melanoma is an aggressive skin cancer with limited treatment options.
- Zerumbone (Zer), a sesquiterpene from Zingiber zerumbet, has shown potential anticancer properties.
- Understanding the molecular mechanisms of Zer's action is crucial for therapeutic development.
Purpose of the Study:
- To evaluate the anticancer efficacy of Zerumbone in human melanoma cells (A375, A2058) and in vivo xenograft models.
- To elucidate the molecular mechanisms underlying Zerumbone-induced cell death, focusing on autophagy and apoptosis.
- To investigate the role of reactive oxygen species (ROS) in Zerumbone's anticancer effects.
Main Methods:
- In vitro studies using A375 and A2058 melanoma cell lines.
- In vivo studies using athymic nude mice xenografted with melanoma cells.
- Analysis of autophagy markers (LC3-II, p62, ATG4B, Beclin-1, AKT/mTOR, AVOs).
- Assessment of apoptosis via caspase activity and TEM.
- Measurement of intracellular ROS levels and intervention with antioxidants (NAC, Mito-Tempo).
Main Results:
- Zerumbone inhibited melanoma cell growth and suppressed EGFR/BRAF expression.
- Zerumbone induced autophagy, evidenced by increased LC3-II, AVO production, and suppressed AKT/mTOR signaling.
- Autophagy inhibition (3-MA, CQ) blocked Zerumbone-induced cell death, while blocking apoptosis enhanced autophagy, indicating autophagy promotes apoptosis.
- Zerumbone triggered ROS generation, and antioxidants reversed its cytotoxic effects.
- Zerumbone significantly suppressed tumor growth in vivo.
Conclusions:
- Zerumbone is a potent antitumor agent against human melanoma.
- Zerumbone-induced cell death is mediated by ROS-dependent autophagy, which subsequently enhances apoptosis.
- Zerumbone exhibits significant anticancer efficacy in both in vitro and in vivo models, warranting further investigation.
