PI3K/AKT/mTOR‐dependent stabilization of oncogenic far‐upstream element binding proteins in hepatocellular carcinoma cells

Abstract

Transcription factors of the far-upstream element-binding protein (FBP) family represent cellular pathway hubs, and their overexpression in liver cancer (hepatocellular carcinoma [HCC]) stimulates tumor cell proliferation and correlates with poor prognosis. Here we determine the mode of oncogenic FBP overexpression in HCC cells. Using perturbation approaches (kinase inhibitors, small interfering RNAs) and a novel system for rapalog-dependent activation of AKT isoforms, we demonstrate that activity of the phosphatidylinositol-4,5-biphosphate 3-kinase/AKT pathway is involved in the enrichment of nuclear FBP1 and FBP2 in liver cancer cells. In human HCC tissues, phospho-AKT significantly correlates with nuclear FBP1/2 accumulation and expression of the proliferation marker KI67. Mechanistic target of rapamycin (mTOR) inhibition or blockade of its downstream effector eukaryotic translation initiation factor 4E activity equally reduced FBP1/2 concentrations. The mTORC1 inhibitor rapamycin diminishes FBP enrichment in liver tumors after hydrodynamic gene delivery of AKT plasmids. In addition, the multikinase inhibitor sorafenib significantly reduces FBP levels in HCC cells and in multidrug resistance 2-deficient mice that develop HCC due to severe inflammation. Both FBP1/2 messenger RNAs are highly stable, with FBP2 being more stable than FBP1. Importantly, inhibition of phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR signaling significantly diminishes FBP1/2 protein stability in a caspase-3/-7-dependent manner. Conclusion These data provide insight into a transcription-independent mechanism of FBP protein enrichment in liver cancer; further studies will have to show whether this previously unknown interaction between phosphatidylinositol-4,5-biphosphate 3-kinase/AKT/mTOR pathway activity and caspase-mediated FBP stabilization allows the establishment of interventional strategies in FBP-positive HCCs.

TRB3 reverses chemotherapy resistance and mediates crosstalk between endoplasmic reticulum stress and AKT signaling pathways in MHCC97H human hepatocellular carcinoma cells

“…Of note, the present study demonstrated that AKT mRNA was decreased in TRB3-knockdown MHCC97H cells. This was in contrast to the findings of a previous study, which suggested that the level of ATK mRNA expression may be upregulated under TRB3 suppression (10). This may be attributed to the specificity of the tumor type.…”

“…Conversely, TRB3 inhibits activation of protein kinase B (AKT) by binding with its threonine or serine activated site, which results in the activation of the downstream signal to induce cell apoptosis (7,8). Furthermore, much of the research in the previous two decades has indicated that the AKT signaling pathway is closely associated with the occurrence and development of hepatic carcinoma (9,10).…”

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

“…Indeed, de novo lipogenesis is activated downstream of the Akt/mTOR pathway, one of the most common signaling pathways altered in cancer. Forced activation of Akt/mTOR induces liver cancer [160, 161], a process mediated at least in part by activation of FASN [155, 156]. Consistently, inactivation of FASN was recently shown to completely inhibit Akt-driven HCC in mice [158].…”

Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross‐talk in hepatocellular carcinoma

“…Hyperactive AKT‐mTOR signaling is a common phenomenon in HCC . Activation of AKT and mTOR is critical for HCG in various common HCC models in mice . However, a recent clinical trial did not achieve desirable endpoints on the rapamycin analog, everolimus, in advanced HCC patients .…”

“…(20,21) Activation of AKT and mTOR is critical for HCG in various common HCC models in mice. (22)(23)(24)(25) However, a recent clinical trial did not achieve desirable endpoints on the rapamycin analog, everolimus, in advanced HCC patients. (26,27) Therefore, identifying new treatment strategies, such as combination therapy, is necessary for improving the efficacy of rapamycin and rapamycin analogs in order to bring mTOR-targeted therapies into the clinic.…”