Inflammation and pancreatic cancer: molecular and functional interactions between S100A8, S100A9, NT-S100A8 and TGFβ1

Cell Communication and Signaling

Research

Sergio Pedrazzoli¹  Michele Scorzeto²  Paola Fogar³  Daniela Basso³  Filippo Navaglia³  Mario Plebani⁴  Dania Bozzato⁵  Carlo-Federico Zambon⁵  Ambrogio Fassina⁵  Michela Pelloso⁵  Stefania Moz⁵  Andrea Padoan⁵  Matteo Fassan⁵  Eliana Greco⁵  Francesca Simonato⁵  Sirio Dupont⁶ 

[1] Associazione Wirsung Onlus, Padova, Italy;Department of Biomedical Sciences – DSB, University of Padova, Padova, Italy;Department of Laboratory Medicine, University-Hospital of Padova, Via Giustiniani 2, 35128, Padova, Italy;Department of Laboratory Medicine, University-Hospital of Padova, Via Giustiniani 2, 35128, Padova, Italy;Department of Medicine – DIMED, University of Padova, Padova, Italy;Department of Medicine – DIMED, University of Padova, Padova, Italy;Department of Molecular Medicine, University of Padova, Padova, Italy;

关键词: Akt;    Calcium;    Calcium binding proteins;    Epithelial to mesenchymal transition;    Mass spectrometry (MS);    Matrix metalloproteinase (MMP);    mTOR;    Pancreatic cancer;    SMAD transcription factor;   

DOI  :  10.1186/1478-811X-12-20

 received in 2013-09-10, accepted in 2014-03-08,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundIn order to gain further insight on the crosstalk between pancreatic cancer (PDAC) and stromal cells, we investigated interactions occurring between TGFβ1 and the inflammatory proteins S100A8, S100A9 and NT-S100A8, a PDAC-associated S100A8 derived peptide, in cell signaling, intracellular calcium (Cai2+) and epithelial to mesenchymal transition (EMT). NF-κB, Akt and mTOR pathways, Cai2+ and EMT were studied in well (Capan1 and BxPC3) and poorly differentiated (Panc1 and MiaPaCa2) cell lines.ResultsNT-S100A8, one of the low molecular weight N-terminal peptides from S100A8 to be released by PDAC-derived proteases, shared many effects on NF-κB, Akt and mTOR signaling with S100A8, but mainly with TGFβ1. The chief effects of S100A8, S100A9 and NT-S100A8 were to inhibit NF-κB and stimulate mTOR; the molecules inhibited Akt in Smad4-expressing, while stimulated Akt in Smad4 negative cells. By restoring Smad4 expression in BxPC3 and silencing it in MiaPaCa2, S100A8 and NT-S100A8 were shown to inhibit NF-κB and Akt in the presence of an intact TGFβ1 canonical signaling pathway. TGFβ1 counteracted S100A8, S100A9 and NT-S100A8 effects in Smad4 expressing, not in Smad4 negative cells, while it synergized with NT-S100A8 in altering Cai2+ and stimulating PDAC cell growth. The effects of TGFβ1 on both EMT (increased Twist and decreased N-Cadherin expression) and Cai2+ were antagonized by S100A9, which formed heterodimers with TGFβ1 (MALDI-TOF/MS and co-immuno-precipitation).ConclusionsThe effects of S100A8 and S100A9 on PDAC cell signaling appear to be cell-type and context dependent. NT-S100A8 mimics the effects of TGFβ1 on cell signaling, and the formation of complexes between TGFβ1 with S100A9 appears to be the molecular mechanism underlying the reciprocal antagonism of these molecules on cell signaling, Cai2+ and EMT.

【 授权许可】

CC BY   
© Basso et al.; licensee BioMed Central Ltd. 2014