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EMBO Mol Med. 2015 Aug;7(8):1048-62. doi: 10.15252/emmm.201404837.

Transcriptional co-factor Transducin beta-like (TBL) 1 acts as a checkpoint in pancreatic cancer malignancy.

Author information

1
Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany.
2
Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany.
3
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany.
4
Medical Research Center, Klinikum Mannheim, Mannheim, Germany.
5
Research Group Cellular Senescence, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
6
Functional Genome Analysis, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
7
Institute of Pathology Heidelberg University, Heidelberg, Germany.
8
Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany Oliver.Strobel@med.uni-heidelberg.de s.herzig@dkfz.de.
9
Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ) Heidelberg Center for Molecular Biology (ZMBH) and University Hospital Heidelberg University, Heidelberg, Germany Institute for Diabetes and Cancer IDC Helmholtz Center Munich and Joint Heidelberg-IDC Translational Diabetes Program, Neuherberg, Germany Oliver.Strobel@med.uni-heidelberg.de s.herzig@dkfz.de.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer fatalities in Western societies, characterized by high metastatic potential and resistance to chemotherapy. Critical molecular mechanisms of these phenotypical features still remain unknown, thus hampering the development of effective prognostic and therapeutic measures in PDAC. Here, we show that transcriptional co-factor Transducin beta-like (TBL) 1 was over-expressed in both human and murine PDAC. Inactivation of TBL1 in human and mouse pancreatic cancer cells reduced cellular proliferation and invasiveness, correlating with diminished glucose uptake, glycolytic flux, and oncogenic PI3 kinase signaling which in turn could rescue TBL1 deficiency-dependent phenotypes. TBL1 deficiency both prevented and reversed pancreatic tumor growth, mediated transcriptional PI3 kinase inhibition, and increased chemosensitivity of PDAC cells in vivo. As TBL1 mRNA levels were also found to correlate with PI3 kinase levels and overall survival in a cohort of human PDAC patients, TBL1 was identified as a checkpoint in the malignant behavior of pancreatic cancer and its expression may serve as a novel molecular target in the treatment of human PDAC.

KEYWORDS:

PI3 kinase; TBL1; gemcitabine; pancreatic cancer; tumor metabolism

PMID:
26070712
PMCID:
PMC4551343
DOI:
10.15252/emmm.201404837
[Indexed for MEDLINE]
Free PMC Article

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