Ovatodiolide suppresses yes-associated protein 1-modulated cancer stem cell phenotypes in highly malignant hepatocellular carcinoma and sensitizes cancer cells to chemotherapy in vitro

Hang Lung Chang, Hsin An Chen, Oluwaseun Adebayo Bamodu, Kwai Fong Lee, Yew Min Tzeng, Wei Hwa Lee, Jo Ting Tsai

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The cancer stem cells (CSCs) theory recently became a focus of heightened attention in cancer biology, with the proposition that CSCs may constitute an important therapeutic target for effective anticancer therapy, because of their demonstrated role in tumor initiation, chemo-, and radio-resistance. Liver CSCs are a small subpopulation of poorly- or undifferentiated liver tumor cells, implicated in tumorigenesis, metastasis, resistance to therapy and disease relapse, enriched with and associated with the functional markers corresponding to the CSCs-enriched side population (SP), high aldehyde dehydrogenase (ALDH) activity, and enhanced formation of in vitro liver CSCs models, referred to herein as hepatospheres. In this study, we found YAP1 was significantly expressed in the SP cells, as well as in generated hepatospheres compared to non-SP or parental HCC cells, at transcript and/or protein levels. In addition, downregulation of YAP1 expression levels by small molecule inhibitor and siRNA transfection, in the HCC cell lines, PLC/PRF/5 and Mahlavu, were associated with marked loss of ability to form hepatospheres and increased sensitivity to sorafenib. Consistent with the above, we demonstrated that YAP1 expression positively correlated with that of Sox2, Oct4, c-Myc and GRP78, markers of stemness and drug resistance. This is suggestive of YAP1’s role as a modulator of cancer stemness, ER stress and chemoresistance. For the first time, we demonstrate that Ovatodiolide significantly attenuates YAP1 expression and subsequently suppressed YAP1-modulated CSCs phenotypes and associated disease progression, consistent with our previous finding in breast cancer. Taken together, our findings suggest that YAP1, highly expressed in malignant liver tumours, contributes to hepatocellular CSCs phenotype and is a molecular target of interest for CSCs targeted therapy in liver cancer patients.

Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalToxicology in Vitro
Volume51
DOIs
Publication statusPublished - Sep 1 2018

Fingerprint

Chemotherapy
Neoplastic Stem Cells
Stem cells
Hepatocellular Carcinoma
Cells
Phenotype
Drug Therapy
Liver
Liver Neoplasms
Neoplasms
Proteins
Tumors
Side-Population Cells
Aldehyde Dehydrogenase
In Vitro Techniques
ovatodiolide
Programmable logic controllers
Cell- and Tissue-Based Therapy
Radio
Drug Resistance

Keywords

  • Cancer stem cells (CSCs)
  • Cancer stemness
  • Chemoresistance
  • Hepatocellular carcinoma
  • Ovatodiolide
  • Side-population
  • YAP1
  • Yes-associated protein

ASJC Scopus subject areas

  • Toxicology

Cite this

Ovatodiolide suppresses yes-associated protein 1-modulated cancer stem cell phenotypes in highly malignant hepatocellular carcinoma and sensitizes cancer cells to chemotherapy in vitro. / Chang, Hang Lung; Chen, Hsin An; Bamodu, Oluwaseun Adebayo; Lee, Kwai Fong; Tzeng, Yew Min; Lee, Wei Hwa; Tsai, Jo Ting.

In: Toxicology in Vitro, Vol. 51, 01.09.2018, p. 74-82.

Research output: Contribution to journalArticle

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T1 - Ovatodiolide suppresses yes-associated protein 1-modulated cancer stem cell phenotypes in highly malignant hepatocellular carcinoma and sensitizes cancer cells to chemotherapy in vitro

AU - Chang, Hang Lung

AU - Chen, Hsin An

AU - Bamodu, Oluwaseun Adebayo

AU - Lee, Kwai Fong

AU - Tzeng, Yew Min

AU - Lee, Wei Hwa

AU - Tsai, Jo Ting

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AB - The cancer stem cells (CSCs) theory recently became a focus of heightened attention in cancer biology, with the proposition that CSCs may constitute an important therapeutic target for effective anticancer therapy, because of their demonstrated role in tumor initiation, chemo-, and radio-resistance. Liver CSCs are a small subpopulation of poorly- or undifferentiated liver tumor cells, implicated in tumorigenesis, metastasis, resistance to therapy and disease relapse, enriched with and associated with the functional markers corresponding to the CSCs-enriched side population (SP), high aldehyde dehydrogenase (ALDH) activity, and enhanced formation of in vitro liver CSCs models, referred to herein as hepatospheres. In this study, we found YAP1 was significantly expressed in the SP cells, as well as in generated hepatospheres compared to non-SP or parental HCC cells, at transcript and/or protein levels. In addition, downregulation of YAP1 expression levels by small molecule inhibitor and siRNA transfection, in the HCC cell lines, PLC/PRF/5 and Mahlavu, were associated with marked loss of ability to form hepatospheres and increased sensitivity to sorafenib. Consistent with the above, we demonstrated that YAP1 expression positively correlated with that of Sox2, Oct4, c-Myc and GRP78, markers of stemness and drug resistance. This is suggestive of YAP1’s role as a modulator of cancer stemness, ER stress and chemoresistance. For the first time, we demonstrate that Ovatodiolide significantly attenuates YAP1 expression and subsequently suppressed YAP1-modulated CSCs phenotypes and associated disease progression, consistent with our previous finding in breast cancer. Taken together, our findings suggest that YAP1, highly expressed in malignant liver tumours, contributes to hepatocellular CSCs phenotype and is a molecular target of interest for CSCs targeted therapy in liver cancer patients.

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