Modulating PI3K/Akt/mTOR-driven autophagy in liver cancer. The role of phytochemicals.

Abstract

Hepatocellular carcinoma is one of the major cancer related causes of mortality all over the world that is mainly caused by successive activation of PI3K/Akt/mTOR signalling axis and subsequent regulation of autophagy by the medium. This review analyses the molecular picture of PI3K/Akt/mTOR pathway in liver cancer, such as PTEN, receptor tyrosine kinase, Akt isoform, mTOR complex, GSK 3Β, CREB, FOXO protein, MDM2 p53 axis, NF kB, and lipid metabolic controller. The dual role of autophagy as a tumour suppressive and tumour promoting process is particularly focused on in regard to the therapeutic resistance to agents like sorafenib. The review summarizes preclinical evidence demonstrating that major classes of phytochemicals, including polyphenols, flavonoids, alkaloids, and terpenoids, target key regulatory components of the PI3K/Akt/mTOR mediated autophagy network. These substances regulate the ULK1 activation, AMPK signalling, reactive oxygen species processes and autophagy crosstalk to apoptosis, and hepatocellular carcinoma model metabolic remodelling. The in vitro and in vivo studies done using the mechanism of action reinforce the idea that phytochemicals are multi target regulators that can restore cytoprotective and cytotoxic autophagy. Finally, the existing challenges in translational research, such as pharmacokinetic issues, biomarker voids, tumour heterogeneity, and resistance, are critically evaluated to set priorities of introducing phytochemicals into the liver cancer treatment in a precision-based fashion.