A combination of AZD5363 and FH5363 induces lethal autophagy in transformed hepatocytes.

Cell Death & Disease
Tapas PatraRanjit Ray

Abstract

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death worldwide. High Akt activation and aberrant β-catenin expression contribute to HCC cell proliferation, stem cell generation, and metastasis. Several signaling pathway-specific inhibitors are in clinical trials and display different efficacies against HCC. In this study, we observed that a β-catenin inhibitor (FH535) displays antiproliferative effect on transformed human hepatocytes (THH). A combination treatment of these cells with FH535 and Akt inhibitor (AZD5363) exerted a stronger effect on cell death. Treatment of THH with AZD5363 and FH535 inhibited cell-cycle progression, enhanced autophagy marker protein expression, and autophagy-associated death, while FH535 treatment alone induced apoptosis. The use of chloroquine or z-VAD further verified these observations. Autophagy flux was evident from lowering marker proteins LAMP2, LAPTM4B, and autophagic protein expression by confocal microscopy using mCherry-EGFP-LC3 reporter construct. A combination treatment with AZD5363 and FH535 enhanced p53 expression, by modulating MDM2 activation; however, AZD5363 treatment alone restricted p53 to the nucleus by inhibiting dynamin-related protein activatio...Continue Reading

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Citations

Mar 7, 2021·International Journal of Molecular Sciences·Mariam MrowehZuzana Macek Jílková
Jul 10, 2021·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·Yuandi DongHaiyang Wang

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Methods Mentioned

BETA
xenograft
flow cytometry
confocal microscopy
transfection
ubiquitination

Software Mentioned

GraphPad Prism
FlowJo

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