Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3β/β-catenin/CDK6 cancer stem pathway

Alexander TH Wu, Yuan Chieh Yeh, Yan Jiun Huang, Ntlotlang Mokgautsi, Bashir Lawal, Tse Hung Huang

Research output: Contribution to journalArticlepeer-review

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 GSK3β-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 GSK3β/CDK6/β-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 GSK3β 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 GSK3β, β-catenin, CDK6, and NF-κB. Therapeutically, we demonstrated that gMG treatment suppressed GSK3β-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/β-catenin/CDK6 and upregulating the miR-26b-5p tumor suppressor. Thus, gMG represents a potential new CRC therapeutic agent and warrants further investigation.

Original languageEnglish
Article number153797
JournalPhytomedicine
Volume95
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • Cancer stem cells (CSCs)
  • Cancer-associated fibroblasts (CAFs)
  • Colorectal cancer (CRC)
  • Cyclin-dependent kinase 6 (CDK6)
  • Gamma-mangostin (gMG)
  • Glycogen synthase kinase 3β (GSK3β)
  • miR-26–5p

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

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