Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α Axis
Liver cancer, consisting mainly of hepatocellular carcinoma, is the third leading cause of cancer-related mortality worldwide. Despite advances in targeted therapies, these approaches remain insufficient in meeting the pressing clinical demands. Here, we present a novel alternative that calls for a...
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MDPI AG
2023-03-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/4/1093 |
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| author | Yichao Gan Chen Wang Yunyun Chen Linxin Hua Hui Fang Shu Li Shoujie Chai Yang Xu Jiawei Zhang Ying Gu |
| author_facet | Yichao Gan Chen Wang Yunyun Chen Linxin Hua Hui Fang Shu Li Shoujie Chai Yang Xu Jiawei Zhang Ying Gu |
| author_sort | Yichao Gan |
| collection | DOAJ |
| description | Liver cancer, consisting mainly of hepatocellular carcinoma, is the third leading cause of cancer-related mortality worldwide. Despite advances in targeted therapies, these approaches remain insufficient in meeting the pressing clinical demands. Here, we present a novel alternative that calls for a non-apoptotic program to solve the current dilemma. Specifically, we identified that tubeimoside 2 (TBM-2) could induce methuosis in hepatocellular carcinoma cells, a recently recognized mode of cell death characterized by pronounced vacuolization, necrosis-like membrane disruption, and no response to caspase inhibitors. Further proteomic analysis revealed that TBM-2-driven methuosis is facilitated by the hyperactivation of the MKK4–p38α axis and the boosted lipid metabolism, especially cholesterol biosynthesis. Pharmacological interventions targeting either the MKK4–p38α axis or cholesterol biosynthesis effectively suppress TBM-2-induced methuosis, highlighting the pivotal role of these mechanisms in TBM-2-mediated cell death. Moreover, TBM-2 treatment effectively suppressed tumor growth by inducing methuosis in a xenograft mouse model of hepatocellular carcinoma. Taken together, our findings provide compelling evidence of TBM-2’s remarkable tumor-killing effects by inducing methuosis, both in vitro and in vivo. TBM-2 represents a promising avenue for the development of innovative and effective therapies for hepatocellular carcinoma, one that may ultimately offer significant clinical benefits for patients with this devastating disease. |
| first_indexed | 2024-03-11T04:38:53Z |
| format | Article |
| id | doaj.art-fc9776c0975e4015bc201cdb018a2ce9 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T04:38:53Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-fc9776c0975e4015bc201cdb018a2ce92023-11-17T20:52:39ZengMDPI AGPharmaceutics1999-49232023-03-01154109310.3390/pharmaceutics15041093Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α AxisYichao Gan0Chen Wang1Yunyun Chen2Linxin Hua3Hui Fang4Shu Li5Shoujie Chai6Yang Xu7Jiawei Zhang8Ying Gu9Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaShanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of Oncology, Ningbo First Hospital, Ningbo 315010, ChinaDepartment of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaCancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, ChinaLiver cancer, consisting mainly of hepatocellular carcinoma, is the third leading cause of cancer-related mortality worldwide. Despite advances in targeted therapies, these approaches remain insufficient in meeting the pressing clinical demands. Here, we present a novel alternative that calls for a non-apoptotic program to solve the current dilemma. Specifically, we identified that tubeimoside 2 (TBM-2) could induce methuosis in hepatocellular carcinoma cells, a recently recognized mode of cell death characterized by pronounced vacuolization, necrosis-like membrane disruption, and no response to caspase inhibitors. Further proteomic analysis revealed that TBM-2-driven methuosis is facilitated by the hyperactivation of the MKK4–p38α axis and the boosted lipid metabolism, especially cholesterol biosynthesis. Pharmacological interventions targeting either the MKK4–p38α axis or cholesterol biosynthesis effectively suppress TBM-2-induced methuosis, highlighting the pivotal role of these mechanisms in TBM-2-mediated cell death. Moreover, TBM-2 treatment effectively suppressed tumor growth by inducing methuosis in a xenograft mouse model of hepatocellular carcinoma. Taken together, our findings provide compelling evidence of TBM-2’s remarkable tumor-killing effects by inducing methuosis, both in vitro and in vivo. TBM-2 represents a promising avenue for the development of innovative and effective therapies for hepatocellular carcinoma, one that may ultimately offer significant clinical benefits for patients with this devastating disease.https://www.mdpi.com/1999-4923/15/4/1093tubeimoside 2methuosishepatocellular carcinomacholesterol biosynthesisp38α |
| spellingShingle | Yichao Gan Chen Wang Yunyun Chen Linxin Hua Hui Fang Shu Li Shoujie Chai Yang Xu Jiawei Zhang Ying Gu Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α Axis Pharmaceutics tubeimoside 2 methuosis hepatocellular carcinoma cholesterol biosynthesis p38α |
| title | Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α Axis |
| title_full | Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α Axis |
| title_fullStr | Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α Axis |
| title_full_unstemmed | Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α Axis |
| title_short | Tubeimoside-2 Triggers Methuosis in Hepatocarcinoma Cells through the MKK4–p38α Axis |
| title_sort | tubeimoside 2 triggers methuosis in hepatocarcinoma cells through the mkk4 p38α axis |
| topic | tubeimoside 2 methuosis hepatocellular carcinoma cholesterol biosynthesis p38α |
| url | https://www.mdpi.com/1999-4923/15/4/1093 |
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