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

• Published in: Toxicology in Vitro Vol. 51; pp. 74 - 82
• Main Authors: Chang, Hang-Lung, Chen, Hsin-An, Bamodu, Oluwaseun Adebayo, Lee, Kwai-Fong, Tzeng, Yew-Min, Lee, Wei-Hwa, Tsai, Jo-Ting
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.09.2018; Elsevier BV; Elsevier Science Ltd
• Subjects: Adaptor Proteins, Signal Transducing; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Aldehyde dehydrogenase; Anticancer properties; Antineoplastic Agents; Antineoplastic Agents - pharmacology; Biomarkers; Breast cancer; c-Myc protein; Cancer; Cancer stem cells (CSCs); Cancer stemness; Carcinoma, Hepatocellular; Carcinoma, Hepatocellular - metabolism; Chemoresistance; Chemotherapy; Disease resistance; Diterpenes; Diterpenes - pharmacology; Drug resistance; Endoplasmic Reticulum Chaperone BiP; Genotype & phenotype; Hepatocellular carcinoma; Hepatocytes; Humans; Liver; Liver cancer; Liver Neoplasms; Liver Neoplasms - metabolism; Metastases; Myc protein; Neoplastic Stem Cells; Niacinamide; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Oct-4 protein; Ovatodiolide; Phenotype; Phenotypes; Phenylurea Compounds; Phenylurea Compounds - pharmacology; Phosphoproteins; Phosphoproteins - genetics; Phosphoproteins - metabolism; Proteins; Side-population; siRNA; Sorafenib; Stem cells; Therapeutic applications; Transcription; Transcription Factors; Transfection; Tumor cells; Tumorigenesis; Tumors; YAP-Signaling Proteins; YAP1; Yes-associated protein; Yes-associated protein; YAP1; Side-population; Chemoresistance; Hepatocellular carcinoma; Cancer stemness; Cancer stem cells (CSCs); Ovatodiolide
• ISSN: 0887-2333; 1879-3177; 1879-3177
• DOI: 10.1016/j.tiv.2018.04.010

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. •Increased YAP1 expression in malignant HCC•Ovatodiolide suppresses HCC stemness.•Ovatodiolide enhances sorafenib's effect via suppressing YAP1