ReferenceID 3187
Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3β/β-catenin/CDK6 cancer stem pathway
Phytomedicine
BACKGROUND: Despite advances in chemotherapies and targeted drugs, colorectal cancer (CRC) remains challenging to treat due to drug resistance. Emerging evidence indicates that cancer-associated fibroblasts (CAFs) facili
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Record Fields
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- Reference Id
- 3187
- Evidence Id
- 19777
- Core Evidence Id
- 19777
- Source Reference Id
- 6355
- Herb2 Reference Id
- HBREF007152
- Subject Paper Key
- HBIN049149_34802869
- Pubmed Id
- 34802869
- Doi
- 10.1016/j.phymed.2021.153797
- Paper Title
- Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3β/β-catenin/CDK6 cancer stem pathway
- Paper Abstract
- BACKGROUND: Despite advances in chemotherapies and targeted drugs, colorectal cancer (CRC) remains challenging to treat due to drug resistance. Emerging evidence indicates that cancer-associated fibroblasts (CAFs) facilitate the generation of cancer stem-like cells (CSCs) and drug resistance. Glycogen synthase kinase-3 (GSK) associated signaling pathways have been implicated in the generation of CSCs and represent a target for therapeutics development. HYPOTHESIS: Gamma-mangostin (gMG) isolated from Garcinia mangostana was evaluated for its ability to downregulate GSK3beta-associated signaling in CRC cells and overcome CAF-induced 5-fluorouracil resistance and CSC generation. METHODS: Bioinformatics analysis, in silico molecular docking, in vitro assays, including cell viability tests, colony- and tumor sphere-formation assays, transwell migration assays, ELISA, SDS-PAGE, Western blotting, miR expression, qPCR, and flow cytometry, as well as in vivo mouse xenograft models were used to evaluate the antitumor effects of gMG. RESULTS: Bioinformatics analyses indicated that GSK3beta/CDK6/beta-catenin mRNA signature was significantly higher in colon cancer patients. Additional algorithms predicted a higher miR-26b level was associated with significantly higher survival in CRC patients and GSK3beta and CDK6 as targets of miR-26b-5p. To validate these findings in vitro, we showed that CAF-cocultured CRC cells expressed an increased expression of GSK3beta, beta-catenin, CDK6, and NF-kappaB. Therapeutically, we demonstrated that gMG treatment suppressed GSK3beta-associated signaling pathways while concomitantly increased the miR-26b-5p level. Using a xenograft mouse model of CAFs cocultured HCT116 tumorspheres, we showed that gMG treatment reduced tumor growth and overcame CAF-induced 5-fluorouracil resistance. CONCLUSIONS: Pharmacological intervention with gMG suppressed CRC carcinogenesis and stemness via downregulating GSK3/beta-catenin/CDK6 and upregulating the miR-26b-5p tumor suppressor. Thus, gMG represents a potential new CRC therapeutic agent and warrants further investigation.
- Journal
- Phytomedicine
- Publish Year
- 2022
- Experiment Subject
- mouse; patient; caf-cocultured crc cells; hct116 tumorspheres
- Experiment Type
- Cell Experiment
- Phenotype Related
- Colon Cancer; Tumor; Colorectal Cancer; Cancer
- Paper Title Cn
- Paper Title En
- Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3β/β-catenin/CDK6 cancer stem pathway
- Bilingual Status
- semi_complete