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.
In HCC cell lines, the AKT-mammalian target of rapamycin complex 1-ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes.
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.
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.
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).
Recently, because of their anti-angiogenic properties, inhibitors of mammalian target of rapamycin (mTOR) have entered clinical trials for therapy of HCC.
Our findings provide a better understanding of the biological activities of the IL-6/PGRN/mTOR cascade in the carcinogenesis of HCC, which may suggest a novel target in the treatment of HCC.
PI3K/mTOR inhibition prevented moderate heat stress-induced global effects on HCC molecular signaling and cellular function, including decreased cell survival, growth, and proliferation (Z-score, -0.3 to -3.2; <i>P</i> < .001) and increased apoptosis and cell death (Z-score, 0.4-1.1; <i>P</i> < .001).ConclusionModerate heat stress induces PI3K/mTOR/AKT-dependent global effects on hepatocellular carcinoma (HCC) cell survival, function, and death.
Prospective clinical trials are needed to test whether the activation status of the mTOR pathway in HCCs predicts the antitumor effect of rapamycin derivative in the posttransplantation course.