Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/β-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas

Wen Chien Huang, Kuang Tai Kuo, Bamodu Oluwaseun Adebayo, Chun Hua Wang, Yu Jen Chen, Ketao Jin, Tung Hu Tsai, Chi Tai Yeh

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Innate or acquired drug resistance and consequent tumor relapse in lung cancer patients have been linked to activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from fruiting bodies of Garcinia indica, and possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory, and anticancer activities, modulates activities of lung CSCs (LCSCs) and their associated aggressiveness. Herein, we demonstrated the inhibitory effect of garcinol on the LCSC phenotype of human NSCLC cells using analytical drug cytotoxicity or cell viability, flow cytometric, and functional assay approaches. Garcinol significantly diminished the ability of the H441 and A549 NSCLC cell lines to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSC viability in dose-dependent manners. Consistent with these observations, flow cytometric data showed that garcinol reduced the putative LCSC pool, evidenced by the dose-dependent decreasing proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In the same assay, garcinol down-regulated β-catenin, Dvl2, Axin2, and cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/β-catenin signaling pathway. The results were further verified in vivo using H441 LCSC mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Taken together, we demonstrated herein that garcinol modulates the LCSC phenotype via regulation of Wnt/β-catenin signaling and inactivation of STAT3, thus showing that garcinol may be a putative novel anti-LCSC therapeutic agent.

Original languageEnglish
Pages (from-to)140-150
Number of pages11
JournalJournal of Nutritional Biochemistry
Volume54
DOIs
Publication statusPublished - Apr 1 2018

Fingerprint

Catenins
Neoplastic Stem Cells
Stem cells
Non-Small Cell Lung Carcinoma
Cells
Phenotype
Assays
Lung Neoplasms
Lung
garcinol
Tumors
Wnt Receptors
Garcinia
Side-Population Cells
Phosphorylation
Wnt Signaling Pathway
Acetyltransferases
Cyclin D1
Cytotoxicity
Drug Resistance

Keywords

  • Anticancer therapy
  • Cancer stem cells
  • Garcinol
  • Non-small cell lung cancer
  • Wnt/β-catenin/STAT3 signaling pathway

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Nutrition and Dietetics
  • Clinical Biochemistry

Cite this

Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/β-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas. / Huang, Wen Chien; Kuo, Kuang Tai; Adebayo, Bamodu Oluwaseun; Wang, Chun Hua; Chen, Yu Jen; Jin, Ketao; Tsai, Tung Hu; Yeh, Chi Tai.

In: Journal of Nutritional Biochemistry, Vol. 54, 01.04.2018, p. 140-150.

Research output: Contribution to journalArticle

@article{5634dcf7ffab4ebb97fe6fbcea06494f,
title = "Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/β-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas",
abstract = "Innate or acquired drug resistance and consequent tumor relapse in lung cancer patients have been linked to activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from fruiting bodies of Garcinia indica, and possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory, and anticancer activities, modulates activities of lung CSCs (LCSCs) and their associated aggressiveness. Herein, we demonstrated the inhibitory effect of garcinol on the LCSC phenotype of human NSCLC cells using analytical drug cytotoxicity or cell viability, flow cytometric, and functional assay approaches. Garcinol significantly diminished the ability of the H441 and A549 NSCLC cell lines to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSC viability in dose-dependent manners. Consistent with these observations, flow cytometric data showed that garcinol reduced the putative LCSC pool, evidenced by the dose-dependent decreasing proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In the same assay, garcinol down-regulated β-catenin, Dvl2, Axin2, and cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/β-catenin signaling pathway. The results were further verified in vivo using H441 LCSC mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Taken together, we demonstrated herein that garcinol modulates the LCSC phenotype via regulation of Wnt/β-catenin signaling and inactivation of STAT3, thus showing that garcinol may be a putative novel anti-LCSC therapeutic agent.",
keywords = "Anticancer therapy, Cancer stem cells, Garcinol, Non-small cell lung cancer, Wnt/β-catenin/STAT3 signaling pathway",
author = "Huang, {Wen Chien} and Kuo, {Kuang Tai} and Adebayo, {Bamodu Oluwaseun} and Wang, {Chun Hua} and Chen, {Yu Jen} and Ketao Jin and Tsai, {Tung Hu} and Yeh, {Chi Tai}",
year = "2018",
month = "4",
day = "1",
doi = "10.1016/j.jnutbio.2017.12.008",
language = "English",
volume = "54",
pages = "140--150",
journal = "Journal of Nutritional Biochemistry",
issn = "0955-2863",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/β-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas

AU - Huang, Wen Chien

AU - Kuo, Kuang Tai

AU - Adebayo, Bamodu Oluwaseun

AU - Wang, Chun Hua

AU - Chen, Yu Jen

AU - Jin, Ketao

AU - Tsai, Tung Hu

AU - Yeh, Chi Tai

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Innate or acquired drug resistance and consequent tumor relapse in lung cancer patients have been linked to activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from fruiting bodies of Garcinia indica, and possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory, and anticancer activities, modulates activities of lung CSCs (LCSCs) and their associated aggressiveness. Herein, we demonstrated the inhibitory effect of garcinol on the LCSC phenotype of human NSCLC cells using analytical drug cytotoxicity or cell viability, flow cytometric, and functional assay approaches. Garcinol significantly diminished the ability of the H441 and A549 NSCLC cell lines to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSC viability in dose-dependent manners. Consistent with these observations, flow cytometric data showed that garcinol reduced the putative LCSC pool, evidenced by the dose-dependent decreasing proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In the same assay, garcinol down-regulated β-catenin, Dvl2, Axin2, and cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/β-catenin signaling pathway. The results were further verified in vivo using H441 LCSC mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Taken together, we demonstrated herein that garcinol modulates the LCSC phenotype via regulation of Wnt/β-catenin signaling and inactivation of STAT3, thus showing that garcinol may be a putative novel anti-LCSC therapeutic agent.

AB - Innate or acquired drug resistance and consequent tumor relapse in lung cancer patients have been linked to activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from fruiting bodies of Garcinia indica, and possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory, and anticancer activities, modulates activities of lung CSCs (LCSCs) and their associated aggressiveness. Herein, we demonstrated the inhibitory effect of garcinol on the LCSC phenotype of human NSCLC cells using analytical drug cytotoxicity or cell viability, flow cytometric, and functional assay approaches. Garcinol significantly diminished the ability of the H441 and A549 NSCLC cell lines to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSC viability in dose-dependent manners. Consistent with these observations, flow cytometric data showed that garcinol reduced the putative LCSC pool, evidenced by the dose-dependent decreasing proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In the same assay, garcinol down-regulated β-catenin, Dvl2, Axin2, and cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/β-catenin signaling pathway. The results were further verified in vivo using H441 LCSC mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Taken together, we demonstrated herein that garcinol modulates the LCSC phenotype via regulation of Wnt/β-catenin signaling and inactivation of STAT3, thus showing that garcinol may be a putative novel anti-LCSC therapeutic agent.

KW - Anticancer therapy

KW - Cancer stem cells

KW - Garcinol

KW - Non-small cell lung cancer

KW - Wnt/β-catenin/STAT3 signaling pathway

UR - http://www.scopus.com/inward/record.url?scp=85041595744&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041595744&partnerID=8YFLogxK

U2 - 10.1016/j.jnutbio.2017.12.008

DO - 10.1016/j.jnutbio.2017.12.008

M3 - Article

VL - 54

SP - 140

EP - 150

JO - Journal of Nutritional Biochemistry

JF - Journal of Nutritional Biochemistry

SN - 0955-2863

ER -