EXPRESS: GANT61, an inhibitor of Gli1, inhibits the proliferation and migration of hepatocellular carcinoma cells.

Constitutive activation of Hedgehog (Hh) signaling has been implicated in many cancers including hepatocellular carcinoma (HCC). Among them, the terminal glioma-associated oncogene homolog 1 (Gli1) regulates the expression of critical genes in the Hh pathway. The current study aims to evaluate the anti-HCC effect of the Gli1 inhibitor, GANT61. In vitro analysis including CCK-8 assay, flow cytometry, migration and invasion assay were adopted to evaluate the effect of GANT61 on HCC cell lines. In vivo xenograft studies were also performed to verify the in vivo effect of GANT61 on HCC. By CCK-8 assay, we found that GANT61 could significantly reduce the growth of HCC cell lines Huh7 and HLE, and their IC50 concentration was 4.481 μM and 6.734 μM, respectively. Flow cytometry shows that GANT61 induced cell cycle arrest in the G2/M phase and accelerated apoptosis of both HLE and Huh7 cells. While migration and invasion assay show that GANT61 weakens cells' migration and invasion ability. Besides that, GANT61 inhibits the expression of Gli1, FoxM1, CyclinD1 and Bcl-2, upregulates the level of Bax protein, and also reverses the epithelial-mesenchymal transition (EMT) program by downregulating the expression of Vimentin and N-Cadherin and upregulating the expression of epithelial E-Cadherin expression. Furthermore, GANT61 inhibits the growth of subcutaneous xenografts of Huh7 cells in nude mice. Overall, this study suggests that Gli1 is a potential target for therapy and GANT61 shows promising therapeutic potential for future treatment in HCC.

Citation

Bao-Wang Liu, Jing-Lin Cao, Yang Wang, Xin Zhao, Qiang Zeng, Wen-Peng Liu, Jun-Hong Zhang, Yi-Ze Fan, Jian Dou. EXPRESS: GANT61, an inhibitor of Gli1, inhibits the proliferation and migration of hepatocellular carcinoma cells. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2023 Sep 19:10815589231204056

PMID: 37724700

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