Nuclear death receptor trail-r2 inhibits maturation of let-7 and promotes proliferation of pancreatic and other tumor cells

Verena Haselmann, Alexandra Kurz, Uwe Bertsch, Sebastian Hübner, Monika Olempska-Müller, Jürgen Fritsch, Robert Häsler, Andreas Pickl, Hendrik Fritsche, Franka Annewanter, Christine Engler, Barbara Fleig, Alexander Bernt, Christian Röder, Hendrik Schmidt, Christoph Gelhaus, Charlotte Hauser, Jan Hendrik Egberts, Carola Heneweer, Anna Maria RohdeChristine Böger, Uwe Knippschild, Christoph Röcken, Dieter Adam, Henning Walczak, Stefan Schütze, Ottmar Janssen, F. Gregory Wulczyn, Harald Wajant, Holger Kalthoff, Anna Trauzold*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Background & Aims Tumor necrosis factor-related apoptosis inducing ligand (TRAIL-R1) (TNFRSF10A) and TRAIL-R2 (TNFRSF10B) on the plasma membrane bind ligands that activate apoptotic and other signaling pathways. Cancer cells also might have TRAIL-R2 in the cytoplasm or nucleus, although little is known about its activities in these locations. We investigated the functions of nuclear TRAIL-R2 in cancer cell lines. Methods Proteins that interact with TRAIL-R2 initially were identified in pancreatic cancer cells by immunoprecipitation, mass spectrometry, and immunofluorescence analyses. Findings were validated in colon, renal, lung, and breast cancer cells. Functions of TRAIL-R2 were determined from small interfering RNA knockdown, real-time polymerase chain reaction, Drosha-activity, microRNA array, proliferation, differentiation, and immunoblot experiments. We assessed the effects of TRAIL-R2 overexpression or knockdown in human pancreatic ductal adenocarcinoma (PDAC) cells and their ability to form tumors in mice. We also analyzed levels of TRAIL-R2 in sections of PDACs and non-neoplastic peritumoral ducts from patients. Results TRAIL-R2 was found to interact with the core microprocessor components Drosha and DGCR8 and the associated regulatory proteins p68, hnRNPA1, NF45, and NF90 in nuclei of PDAC and other tumor cells. Knockdown of TRAIL-R2 increased Drosha-mediated processing of the let-7 microRNA precursor primary let-7 (resulting in increased levels of mature let-7), reduced levels of the let-7 targets (LIN28B and HMGA2), and inhibited cell proliferation. PDAC tissues from patients had higher levels of nuclear TRAIL-R2 than non-neoplastic pancreatic tissue, which correlated with increased nuclear levels of HMGA2 and poor outcomes. Knockdown of TRAIL-R2 in PDAC cells slowed their growth as orthotopic tumors in mice. Reduced nuclear levels of TRAIL-R2 in cultured pancreatic epithelial cells promoted their differentiation. Conclusions Nuclear TRAIL-R2 inhibits maturation of the microRNA let-7 in pancreatic cancer cell lines and increases their proliferation. Pancreatic tumor samples have increased levels of nuclear TRAIL-R2, which correlate with poor outcome of patients. These findings indicate that in the nucleus, death receptors can function as tumor promoters and might be therapeutic targets.

Original languageEnglish (US)
Pages (from-to)278-290
Number of pages13
JournalGastroenterology
Volume146
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Apoptosis Regulation
  • MALDI-TOF
  • microRNA Processing
  • Pancreatic Cancer

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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