Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Metabolic reprogramming is considered a new hallmark of cancer, but it remains unclearly described in HCC. The dysregulation of the PI3K/AKT/mTOR signaling pathway is common in HCC and is, therefore, a topic of further research and the concern of developing a novel target for liver cancer therapy. In this review, we illustrate mechanisms by which this signaling network is accountable for regulating HCC cellular metabolism, including glucose metabolism, lipid metabolism, amino acid metabolism, pyrimidine metabolism, and oxidative metabolism, and summarize the ongoing clinical trials based on the inhibition of the PI3K/AKT/mTOR pathway in HCC.

Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is related to risk factors such as viral hepatitis, alcohol intake, and non-alcoholic fatty liver disease (NAFLD). The constitutive activation of the PI3K/AKT signaling pathway is common in HCC and has essential involvement in tumor progression. The serine/threonine kinase AKT has several downstream substrates, which have been implicated in the regulation of cellular metabolism. However, the contribution of each of the three AKT isoforms, i.e., AKT1, AKT2 and AKT3, to HCC metabolism has not been comprehensively investigated. In this study, we analyzed the functional role of AKT1, AKT2 and AKT3 in HCC metabolism. The overexpression of activated AKT1, AKT2 and AKT3 isoforms in the human HCC cell lines Hep3B and Huh7 resulted in higher oxygen consumption rate (OCR), ATP production, maximal respiration and spare respiratory capacity in comparison to vector-transduced cells. Vice versa, lentiviral vector-mediated knockdowns of each AKT isoform reduced OCR in both cell lines. Reduced OCR rates observed in the three AKT isoform knockdowns were associated with reduced extracellular acidification rates (ECAR) and reduced lactate production in both analyzed cell lines. Mechanistically, the downregulation of OCR by AKT isoform knockdowns correlated with an increased phosphorylation of the pyruvate dehydrogenase on Ser232, which negatively regulates the activity of this crucial gatekeeper of mitochondrial respiration. In summary, our data indicate that each of the three AKT isoforms is able to upregulate OCR, ECAR and lactate production independently of each other in human HCC cells through the regulation of the pyruvate dehydrogenase.

Background/Objectives: AKT signaling is a central regulator of cancer metabolism; however, the isoform-specific roles of AKT1, AKT2, and AKT3 in fatty acid metabolism remain incompletely understood in hepatocellular carcinoma (HCC). This study aimed to investigate the contributions of individual AKT isoforms to fatty acid regulation in an HCC cells model. Methods: Stable knockdown models of AKT1, AKT2, and AKT3 were established in Mahlavu cells, whereas stable knockdown models of AKT1 and AKT2 were established in Huh7 cells because endogenous AKT3 expression was very low. Targeted fatty acid profiling was performed using gas chromatography–mass spectrometry (GC–MS) to evaluate alterations in fatty acid composition following AKT isoform knockdown. Results: Knockdown of AKT1, AKT2, and AKT3 in Mahlavu cells, and AKT1 and AKT2 in Huh7 cells, was associated with reduced relative abundance of several common fatty acids, including myristic acid (C14:0), myristoleic acid (C14:1), 7-hexadecenoic acid (C16:1), arachidic acid (C20:0), eicosenoic acid (C20:1), and erucic acid (C22:1). In addition, isoform-specific differences in fatty acids composition were also observed in both HCC cell lines. Compared with scrambled control cells, knockdown of AKT1 or AKT3, but not AKT2, was associated with significant reductions in palmitic acid (C16:0) and stearic acid (C18:0) in Mahlavu cells. In contrast, Huh7 cells exhibited distinct changes in fatty acid composition, showing unchanged or increased relative abundance of palmitic acid (C16:0) and stearic acid (C18:0) following AKT1 or AKT2 knockdown. Moreover, in Huh7 cells very-long-chain fatty acids (VLCFAs), behenic acid (C22:0) and nervonic acid (C24:1) were significantly reduced following AKT2 knockdown, but not AKT1 knockdown. Conclusions: These findings suggest that AKT isoforms play a role regarding fatty acid composition in HCC cells, with both shared and isoform-associated patterns which should be investigated in further studies.