Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade

• Published in: PloS one 2017-09, Vol.12 (9), p.e0184068
• Main Authors: Jia, Jiaoyuan, Qiao, Yu, Pilo, Maria G, Cigliano, Antonio, Liu, Xianqiong, Shao, Zixuan, Calvisi, Diego F, Chen, Xin
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Antineoplastic Agents - therapeutic use; Antineoplastic drugs; Antitumor agents; Apoptosis; Apoptosis - drug effects; Bioengineering; Biology and Life Sciences; Biotechnology; Blotting, Western; Carcinoma, Hepatocellular - drug therapy; Carrier Proteins - metabolism; Cell cycle; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Complications and side effects; Development and progression; Dosage and administration; Dose-Response Relationship, Drug; Drugs; Gastroenterology; Gene expression; Hepatocellular carcinoma; Heterocyclic Compounds, 3-Ring - therapeutic use; Human performance; Humans; Inhibitors; Liver cancer; Liver Neoplasms - drug therapy; Medicine; Medicine and Health Sciences; Membrane Proteins - metabolism; Molecular modelling; Pathology; Patient outcomes; Penicillin; Pharmacy; Phosphoproteins - metabolism; Prognosis; Proteins; Real-Time Polymerase Chain Reaction; Regulators; Rodents; Sorafenib; Sulfones - therapeutic use; Tankyrases - antagonists & inhibitors; Transcription Factors; Triazoles - therapeutic use; Tumor cell lines; Tumors; Yes-associated protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0184068

Previous data indicate that Tankyrase inhibitors exert anti-growth functions in many cancer cell lines due to their ability to inactivate the YAP protooncogene. In the present manuscript, we investigated the effect of Tankyrase inhibitors on the growth of hepatocellular carcinoma (HCC) cell lines and the molecular mechanisms involved. For this purpose, we performed cell proliferation assay by colony-forming ability in seven human HCC cells subjected to XAV-939 and G007-LK Tankyrase inhibitors. Noticeably, the two Tankyrase inhibitors suppressed the HCC cell growth in a dose-dependent manner. Furthermore, we found that Tankyrase inhibitors synergized with MEK and AKT inhibitors to suppress HCC cell proliferation. At the molecular level, Tankyrase inhibitors significantly decreased YAP protein levels, reduced the expression of YAP target genes, and inhibited YAP/TEAD luciferase reporter activity. In addition, Tankyrase inhibitors administration was accompanied by upregulation of Angiomotin-like 1 (AMOTL1) and Angiomotin-like 2 (AMOTL2) proteins, two major negative regulators of YAP. Altogether, the present data indicate that XAV-939 and G007-LK Tankyrase inhibitors could suppress proliferation of hepatocellular carcinoma cells and downregulate YAP/TAZ by stabilizing AMOTL1 and AMOTL2 proteins, thus representing new potential anticancer drugs against hepatocellular carcinoma.