Hyperglycemia-Induced S100A8 and S100A9 Target Akt and NF-kB Signalling in Pancreatic Cancer Cells.

Context In pancreatic cancer (PaCa) S100A8 is highly expressed by stromal cells when SMAD4 is not mutated or by cancer cells when SMAD4 is mutated, suggesting the existence of a link between TGF-b and S100A8 pathways. Moreover S100A8 and its binding partner S100A9 are suggested to be involved in cancer progression and in cancer-associated diabetes mellitus. Objectives To analyze S100A8 and S100A9 expression levels in peripheral blood mononuclear cells of patients with PaCa, chronic pancreatitis (ChrPa) or pancreatobiliary tract tumors (PBT) and to ascertain S100A8/S100A9 interactions with TGF-b1 on PaCa Akt and NF-kB signalling. Methods Fifty-five PaCa, 12 ChrPa and 15 PBT were studied. S100A8 and S100A9 mRNA expression levels were quantified by RT-PCR (Taqman chemistry). Capan-1 (SMAD4 mutated) and MiaPaCa2 (SMAD4 wild type) cell lines were used to analyze S100A8, S100A9 and TGF-b1 effects on Akt (pAkt473) and NF-kB (pIkBa) signalling by western blotting. Results S100A8 and S100A9 expression levels were correlated with each other (r=0.637, P<0.0001), but none of these proteins vary between groups (F=0.65, P NS; F=2.75, P NS) or, in PaCa, between tumor stage (t=1.24, P NS; t=0.56, P NS). S100A8, but mainly S100A9, were directly correlated with fasting plasma glucose (r=0.22, P=0.05; r=0.46, P<0.0001), HbA1c (r=0.11, P NS; r=0.37, P=0.002), and insulin (0.37, P=0.008; r=0.46, P=0.001). The heterocomplex S100A8/S100A9, not any single molecule, induced Akt473 phosphorylation, which was enhanced by TGF-b1. IkBa phosphorylation of MiaPaCa 2 was slightly affected by S100A9 treatment only. In Capan-1 S100A8 was ineffective, while S100A9 and S100A8/S100A9 complex induced a highly significant increase of IkBa phosphorylation, which was not modified by TGF-b1. Conclusions Blood expression levels of S100A8 and S100A9 do not reflect the presence of malignancy, but a poor glycemic control. In PaCa associated diabetes mellitus higher levels of these proteins might favour cancer cell growth by inducing Akt and NF-kB signalling. TGF-b1 might act as a S100A8/S100A9 co-factor when SMAD4 mutations occur.