期刊
PHYTOMEDICINE
卷 102, 期 -, 页码 -出版社
ELSEVIER GMBH
DOI: 10.1016/j.phymed.2022.154164
关键词
6-ME; PCD; RIPK1/caspases/GSDME; OAA metabolism; ROS; PC intervention
资金
- National Natural Science Foundation of China [81902803]
- Project of Zhejiang Provincial Naturel Science Foundation of China [LY21H160057, LQ21H160043, Q22H312636]
- Science and Technology Bureau of Wenzhou [Y20190069, Y2020208]
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province [7K0029]
In this study, researchers found that a novel alkaloid named 6-methoxy dihydrosphingosine (6-ME) extracted from M. cordata fruits effectively inhibited the growth of pancreatic cancer cells and promoted apoptosis. The anti-tumor effects of 6-ME were achieved by disrupting OAA metabolism and increasing ROS production, leading to mitochondrial dysfunction and cell death.
Background: Many extracts and purified alkaloids of M. cordata (Papaveraceae family) have been reported to display promising anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis in many cancer types. However, no evidence currently exists for anti-pancreatic cancer activity of alkaloids extracted from M. cordata, including a novel alkaloid named 6-methoxy dihydrosphingosine (6-Methoxydihydroavicine, 6-ME) derived from M. cordata fruits. Purpose: The aim of this study was to investigate the anti-tumor effects of 6-ME on PC cells and the underlying mechanism. Methods: CCK-8, RTCA, and colony-formation assays were used to analyze PC cell growth. Cell death ratios, changes in MMP and ROS levels were measured by flow cytometry within corresponding detection kits. A Seahorse XFe96 was employed to examine the effects of 6-ME on cellular bioenergetics. Western blot and q-RT-PCR were conducted to detect changes in target molecules. Results: 6-ME effectively reduced the growth of PC cells and promoted PCD by activating RIPK1, caspases, and GSDME. Specifically, 6-ME treatment caused a disruption of OAA metabolism and increased ROS production, thereby affecting mitochondrial homeostasis and reducing aerobic glycolysis. These responses resulted in mitophagy and RIPK1-mediated cell death. Conclusion: 6-ME exhibited specific anti-tumor effects through interrupting OAA metabolic homeostasis to trigger ROS/RIPK1-dependent cell death and mitochondrial dysfunction, suggesting that 6-ME could be considered as a highly promising compound for PC intervention.
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