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

Christian Stoy, Aishwarya Sundaram, Marcos Rios Garcia, Xiaoyue Wang, Oksana Seibert, Annika Zota, Susann Wendler, David Männle, Ulf Hinz, Carsten Sticht, Maria Muciek, Norbert Gretz, Adam J. Rose, Vera Greiner, Thomas G. Hofmann, Andrea Bauer, Jörg Hoheisel, Mauricio Berriel Diaz, Matthias M. Gaida, Jens WernerTobias Schafmeier, Oliver Strobel, Stephan Herzig

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish
Pages (from-to)1048-1062
Number of pages15
JournalEMBO Molecular Medicine
Volume7
Issue number8
DOIs
StatePublished - 1 Aug 2015
Externally publishedYes

Keywords

  • Gemcitabine
  • PI3 kinase
  • Pancreatic cancer
  • TBL1
  • Tumor metabolism

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