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Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY323). This alternative p38 activation pathway is required for pro-inflammatory cytokine production. Here we show in human PDAC that a high percentage of infiltrating pY323(+) T cells was associated with large numbers of tumor necrosis factor (TNF)-?- and interleukin (IL)-17-producing CD4(+) tumor-infiltrating lymphocytes (TILs) and aggressive disease. The growth of mouse pancreatic tumors was inhibited by genetic ablation of the alternative p38 pathway, and transfer of wild-type CD4(+) T cells, but not those lacking the alternative pathway, enhanced tumor growth in T cell-deficient mice. Notably, a plasma membrane-permeable peptide derived from GADD45-?, the naturally occurring inhibitor of p38 pY323(+) (ref. 7), reduced CD4(+) TIL production of TNF-?, IL-17A, IL-10 and secondary cytokines, halted growth of implanted tumors and inhibited progression of spontaneous KRAS-driven adenocarcinoma in mice. Thus, TCR-mediated activation of CD4(+) TILs results in alternative p38 activation and production of protumorigenic factors and can be targeted for therapeutic benefit.

SUBMITTER: Alam MS

PROVIDER: S-EPMC4636461 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression.

Alam Muhammad S MS Gaida Matthias M MM Bergmann Frank F Lasitschka Felix F Giese Thomas T Giese Nathalia A NA Hackert Thilo T Hinz Ulf U Hussain S Perwez SP Kozlov Serguei V SV Ashwell Jonathan D JD

Nature medicine 20151019 11

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive neoplasm characterized by a marked fibro-inflammatory microenvironment, the presence of which can promote both cancer induction and growth. Therefore, selective manipulation of local cytokines is an attractive, although unrealized, therapeutic approach. T cells possess a unique mechanism of p38 mitogen-activated protein kinase (MAPK) activation downstream of T cell receptor (TCR) engagement through the phosphorylation of Tyr323 (pY32 ...[more]

PMID: 26479921

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Project description:Ubiquitin D (UBD), a member of the ubiquitin‑like modifier family, has been reported to be highly expressed in various types of cancer and its overexpression is positively associated with tumor progression. However, the role and mechanism of UBD in rheumatoid arthritis (RA) remain elusive. In the present study, the gene expression profiles of GSE55457 were downloaded from the Gene Expression Omnibus database to assess differentially expressed genes and perform functional enrichment analyses. UBD was overexpressed by lentivirus transfection. The protein level of UBD, p‑p38 and p38 in RA‑fibroblast‑like synoviocytes (FLSs) were examined by western blotting. Cell Counting Kit‑8 and flow cytometry assays were used to detect the functional changes of RA‑FLSs transfected with UBD and MAPK inhibitor SB202190. The concentrations of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α) were evaluated using ELISA kits. The results revealed that UBD was overexpressed in RA tissues compared with in the healthy control tissues. Functionally, UBD significantly accelerated the viability and proliferation of RA‑FLSs, whereas it inhibited their apoptosis. Furthermore, UBD significantly promoted the secretion of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α). Mechanistically, elevated UBD activated phospohorylated‑p38 in RA‑FLSs. By contrast, UBD overexpression and treatment with the p38 MAPK inhibitor SB202190 not only partially relieved the UBD‑dependent effects on cell viability and proliferation, but also reversed its inhibitory effects on cell apoptosis. Furthermore, SB202190 partially inhibited the effects of UBD overexpression on the enhanced secretion of inflammatory factors. The present study indicated that UBD may mediate the activation of p38 MAPK, thereby facilitating the proliferation of RA‑FLSs and ultimately promoting the progression of RA. Therefore, UBD may be considered a potential therapeutic target and a promising prognostic biomarker for RA.

Dataset Information

Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression.

Publications

Selective inhibition of the p38 alternative activation pathway in infiltrating T cells inhibits pancreatic cancer progression.

Similar Datasets

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