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

Jana Samarin; Vibor Laketa; Mona Malz; Stephanie Roessler; Ilan Stein; Elad Horwitz; Stephan Singer; Eleni Dimou; Antonio Cigliano; Michaela Bissinger; Christine Susanne Falk; Xin Chen; Steven Dooley; Eli Pikarsky; Diego Francesco Calvisi; Carsten Schultz; Peter Schirmacher; Kai Breuhahn

doi:10.1002/hep.28357

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

Jana Samarin, Vibor Laketa, Mona Malz, Stephanie Roessler, Ilan Stein, Elad Horwitz, Stephan Singer, Eleni Dimou, Antonio Cigliano, Michaela Bissinger, Christine Susanne Falk, Xin Chen, Steven Dooley, Eli Pikarsky, Diego Francesco Calvisi, Carsten Schultz, Peter Schirmacher, Kai Breuhahn^*

^*Corresponding author for this work

Department of Immunology and Cancer Research

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

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.

Original language	American English
Pages (from-to)	813-826
Number of pages	14
Journal	Hepatology
Volume	63
Issue number	3
DOIs	https://doi.org/10.1002/hep.28357
State	Published - 1 Mar 2016

Bibliographical note

Publisher Copyright:
© 2016 by the American Association for the Study of Liver Diseases.

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10.1002/hep.28357

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Samarin, J., Laketa, V., Malz, M., Roessler, S., Stein, I., Horwitz, E., Singer, S., Dimou, E., Cigliano, A., Bissinger, M., Falk, C. S., Chen, X., Dooley, S., Pikarsky, E., Calvisi, D. F., Schultz, C., Schirmacher, P., & Breuhahn, K. (2016). PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells. Hepatology, 63(3), 813-826. https://doi.org/10.1002/hep.28357

@article{528de9a8cd134972801a442a4a96caea,

title = "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.",

author = "Jana Samarin and Vibor Laketa and Mona Malz and Stephanie Roessler and Ilan Stein and Elad Horwitz and Stephan Singer and Eleni Dimou and Antonio Cigliano and Michaela Bissinger and Falk, {Christine Susanne} and Xin Chen and Steven Dooley and Eli Pikarsky and Calvisi, {Diego Francesco} and Carsten Schultz and Peter Schirmacher and Kai Breuhahn",

note = "Publisher Copyright: {\textcopyright} 2016 by the American Association for the Study of Liver Diseases.",

year = "2016",

month = mar,

day = "1",

doi = "10.1002/hep.28357",

language = "American English",

volume = "63",

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Samarin, J, Laketa, V, Malz, M, Roessler, S, Stein, I, Horwitz, E, Singer, S, Dimou, E, Cigliano, A, Bissinger, M, Falk, CS, Chen, X, Dooley, S, Pikarsky, E, Calvisi, DF, Schultz, C, Schirmacher, P & Breuhahn, K 2016, 'PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells', Hepatology, vol. 63, no. 3, pp. 813-826. https://doi.org/10.1002/hep.28357

TY - JOUR

T1 - PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells

AU - Samarin, Jana

AU - Laketa, Vibor

AU - Malz, Mona

AU - Roessler, Stephanie

AU - Stein, Ilan

AU - Horwitz, Elad

AU - Singer, Stephan

AU - Dimou, Eleni

AU - Cigliano, Antonio

AU - Bissinger, Michaela

AU - Falk, Christine Susanne

AU - Chen, Xin

AU - Dooley, Steven

AU - Pikarsky, Eli

AU - Calvisi, Diego Francesco

AU - Schultz, Carsten

AU - Schirmacher, Peter

AU - Breuhahn, Kai

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84954306240&partnerID=8YFLogxK

U2 - 10.1002/hep.28357

DO - 10.1002/hep.28357

M3 - Article

C2 - 26901106

AN - SCOPUS:84954306240

SN - 0270-9139

VL - 63

SP - 813

EP - 826

JO - Hepatology

JF - Hepatology

IS - 3

ER -

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

Abstract

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