Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells.
10.1016/j.joim.2025.04.006
- Author:
Yi WANG
1
;
Xiao-Yu SUN
1
;
Fang-Qi MA
1
;
Ming-Ming REN
1
;
Ruo-Han ZHAO
1
;
Meng-Meng QIN
1
;
Xiao-Hong ZHU
1
;
Yan XU
1
;
Ni-da CAO
1
;
Yuan-Yuan CHEN
2
;
Tian-Geng DONG
3
;
Yong-Fu PAN
4
;
Ai-Guang ZHAO
5
Author Information
1. Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
2. Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
3. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
4. Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: yongfupan11@fudan.edu.cn.
5. Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China. Electronic address: lh2305@shutcm.edu.cn.
- Publication Type:Journal Article
- Keywords:
ABT-737;
Apoptosis;
BCL-2-associated agonist of cell death;
Gastric cancer;
Morin;
Ubiquitination degradation
- MeSH:
Humans;
Flavonoids/therapeutic use*;
Stomach Neoplasms/pathology*;
Animals;
Proto-Oncogene Proteins c-bcl-2/metabolism*;
Cell Line, Tumor;
Apoptosis/drug effects*;
Cell Proliferation/drug effects*;
Ubiquitination/drug effects*;
Mice;
Drug Synergism;
Mice, Inbred BALB C;
Mice, Nude;
Xenograft Model Antitumor Assays;
Flavones
- From:
Journal of Integrative Medicine
2025;23(3):320-332
- CountryChina
- Language:English
-
Abstract:
OBJECTIVE:Gastric cancer (GC) is one of the most common malignancies seen in clinic and requires novel treatment options. Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L., which exhibits an anti-cancer effect in multiple types of tumors. However, the therapeutic effect and underlying mechanism of morin in treating GC remains elusive. The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC.
METHODS:For in vitro experiments, the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45, human gastric adenocarcinoma cell line AGS, and human gastric epithelial cell line GES-1; for apoptosis analysis, microscopic photography, Western blotting, ubiquitination analysis, quantitative polymerase chain reaction analysis, flow cytometry, and RNA interference technology were employed. For in vivo studies, immunohistochemistry, biomedical analysis, and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC.
RESULTS:Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose- and time-dependent manner, but did not inhibit human gastric epithelial cells GES-1. Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells, suggesting that apoptosis was the main type of cell death during the treatment. Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells, which mainly relied on B cell leukemia/lymphoma 2 (BCL-2) associated agonist of cell death (BAD) but not phorbol-12-myristate-13-acetate-induced protein 1. The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD, rather than the transcription regulation and the phosphorylation of BAD. Furthermore, the combination of morin and BCL-2 inhibitor navitoclax (also known as ABT-737) produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals. In addition, morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway.
CONCLUSION:Morin suppressed GC by inducing apoptosis, which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD. The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells, which may overcome the drug resistance of the BCL-2 inhibitor. These findings indicated that morin was a potent and promising agent for GC treatment. Please cite this article as: Wang Y, Sun XY, Ma FQ, Ren MM, Zhao RH, Qin MM, Zhu XH, Xu Y, Cao ND, Chen YY, Dong TG, Pan YF, Zhao AG. Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells. J Integr Med. 2025; 23(3): 320-332.
