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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

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

Jiaoyuan Jia1,2, Yu Qiao2,3, Maria G Pilo4

  • 1Department of Oncology and Hematology, The Second Hospital, Jilin University, Changchun, China.

Plos One
|September 7, 2017
PubMed

Insights

Tankyrase inhibitors XAV-939 and G007-LK effectively suppressed hepatocellular carcinoma (HCC) cell growth. These inhibitors downregulate YAP/TAZ by stabilizing AMOTL1 and AMOTL2, showing potential as HCC anticancer drugs.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tankyrase inhibitors are known to inhibit cancer cell growth by inactivating the YAP protooncogene.
  • Hepatocellular carcinoma (HCC) is a significant global health concern with a need for novel therapeutic strategies.

Purpose of the Study:

  • To investigate the anti-proliferative effects of Tankyrase inhibitors (XAV-939 and G007-LK) on hepatocellular carcinoma (HCC) cell lines.
  • To elucidate the molecular mechanisms underlying the action of Tankyrase inhibitors in HCC.

Main Methods:

  • Cell proliferation assay using colony-forming ability in seven human HCC cell lines treated with XAV-939 and G007-LK.
  • Analysis of YAP protein levels, YAP target gene expression, and YAP/TEAD luciferase reporter activity.
  • Assessment of Angiomotin-like 1 (AMOTL1) and Angiomotin-like 2 (AMOTL2) protein levels.

Main Results:

  • Both XAV-939 and G007-LK Tankyrase inhibitors demonstrated dose-dependent suppression of HCC cell growth.
  • Tankyrase inhibitors synergized with MEK and AKT inhibitors to further inhibit HCC cell proliferation.
  • Inhibitors decreased YAP protein levels, reduced YAP target gene expression, and inhibited YAP/TEAD activity, while upregulating AMOTL1 and AMOTL2.

Conclusions:

  • XAV-939 and G007-LK Tankyrase inhibitors effectively suppress HCC cell proliferation.
  • The mechanism involves YAP/TAZ downregulation through the stabilization of AMOTL1 and AMOTL2 proteins.
  • These Tankyrase inhibitors represent promising novel therapeutic agents for hepatocellular carcinoma treatment.

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