Choline Kinase α Mediates Interactions Between the Epidermal Growth Factor Receptor and Mechanistic Target of Rapamycin Complex 2 in Hepatocellular Carcinoma Cells to Promote Drug Resistance and Xenograft Tumor Progression.
This study was conducted to determine the status of the mTOR pathway in human hepatocellular carcinoma (HCC) and to investigate its relationship with the prognosis of HCC.
Tumor cells from these mice demonstrated high activity of the AKT/ mammalian target of rapamycin (mTOR) and Ras/ Mitogen-activated protein kinase (MAPK) signaling cascades, two pathways frequently co-induced in human HCC.
Through protein and histological analyzes we observed activation of these pathways in human HCC, suggesting that targeting both mTOR and Src may be a novel approach for the treatment of HCC.
Although the review focuses on the mTOR pathway involved in HCC, more comprehensive discussions (eg, developing a rational design for future trials targeting the mTOR pathway) are also applicable to other tumors.
Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2)-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1)-inhibition has no impact.
Anthracimycin is a novel mTOR inhibitor capable of suppressing the proliferation of CSCs and non-CSCs equally well in HCC, and it is suggested that anthracimycin could be effective in the eradication of HCC associated with mTOR-signaling activation.
We have shown previously that rapamycin, the canonical inhibitor of the mechanistic target of rapamycin (mTOR) complex 1, markedly inhibits the growth of focal lesions in the resistant hepatocyte (Solt-Farber) model of hepatocellular carcinoma (HCC) in the rat.
Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence.
The association of metabolic syndrome with HBV-related HCC raises the possibility that pre-S2 mutant-induced MTOR activation may drive the development of metabolic disorders to promote tumorigenesis in chronic HBV infection.
Immunohistochemical analysis showed that mTOR was characteristically phosphorylated in liver tumors of TSOD mice and HCCs from metabolic syndrome cases in humans.
Suppression of LKB1 or promotion of AMP by metformin also abrogated the hyperproliferative phenotype caused by SIRT4 loss, which further confirmed that the LKB1/AMPKα/mTOR axis is required in SIRT4-deficiency-promoted HCC tumorigenesis.
Furthermore, protein levels of IGF-1R and mTOR were found to be inversely correlated with miR-99a expression in HCC tissues. miR-99a mimics inhibited IGF-1R and mTOR pathways and subsequently suppressed expression of cell cycle-related proteins, including cyclin D1 in HCC cells.
These results suggest that mTOR-STAT3-HK2 pathway is involved in the glycolysis of HCC cells and STAT3 may regulate HCC glycolysis through HK2 pathway, providing potential multiple therapeutic targets through intervention of glycolysis for the treatment of HCC.
The interactions between mTOR kinase inhibitors (mTORKis) (i.e., Pp242, AZD8055, OSI027) and HDACis (i.e., SAHA, LBH589) were examined in vitro using HCC cell lines and in vivo using patient-derived primary HCC xenografts on SCID mice.
Obesity-induced insulin resistance depends, in part, on chronic activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer.
Many novel agents are under investigation in phase III trials in advanced HCC, including antiangiogenic multikinase inhibitors (e.g., brivanib, sunitinib, linifanib) and inhibitors of the mammalian target of rapamycin (mTOR) pathway (e.g., everolimus).
Given the key role of mammalian target of rapamycin (mTOR) signaling in HCC progression, we also tested whether ARHI overexpression affected the mTOR pathway.