TY - JOUR
T1 - Gamma-mangostin isolated from garcinia mangostana suppresses colon carcinogenesis and stemness by downregulating the GSK3β/β-catenin/CDK6 cancer stem pathway
AU - Wu, Alexander TH
AU - Yeh, Yuan Chieh
AU - Huang, Yan Jiun
AU - Mokgautsi, Ntlotlang
AU - Lawal, Bashir
AU - Huang, Tse Hung
N1 - Funding Information:
Alexander TH Wu is funded by Taipei Medical University ( DP2-110-21121-03-C-09 ); Tse-Hung Huang is funded by the following sources: CMRPG2H0362, CORPG2J0042, CMRPG2G0333 CMRPG2K0031 and CMRPG2H0121.
Funding Information:
Alexander TH Wu is funded by Taipei Medical University (DP2-110-21121-03-C-09); Tse-Hung Huang is funded by the following sources: CMRPG2H0362, CORPG2J0042, CMRPG2G0333 CMRPG2K0031 and CMRPG2H0121. Yuan-Chieh Yeh issupported by MOST 107-2320-B-182A-019-MY3. Not applicable. No human samples were used in this study.
Publisher Copyright:
© 2021 Elsevier GmbH
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - Cancer stem cells (CSCs)
KW - Cancer-associated fibroblasts (CAFs)
KW - Colorectal cancer (CRC)
KW - Cyclin-dependent kinase 6 (CDK6)
KW - Gamma-mangostin (gMG)
KW - Glycogen synthase kinase 3β (GSK3β)
KW - miR-26–5p
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U2 - 10.1016/j.phymed.2021.153797
DO - 10.1016/j.phymed.2021.153797
M3 - Article
AN - SCOPUS:85119588658
SN - 0944-7113
VL - 95
JO - Phytomedicine
JF - Phytomedicine
M1 - 153797
ER -
