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Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression.

ABSTRACT: BACKGROUND AND PURPOSE:Dipeptidyl peptidase 4 (DPP4) is an aminopeptidase that is widely expressed in different cell types. Recent studies suggested that DPP4 plays an important role in tumour progression in several human malignancies. Here we have examined the mechanisms by which up-regulation of DPP4 expression causes epithelial transformation and mammary tumourigenesis. EXPERIMENTAL APPROACH:Expression of DPP4 and the peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1), and the cytotoxic effects of combined treatment with sitagliptin and juglone were investigated by immunohistochemistry, immunoblotting, real-time PCR, TUNEL and soft agar assays, using MCF7 cells. The effects of sitagliptin on tumour development in vivo were studied in the syngeneic 4T1 metastatic breast cancer model. KEY RESULTS:Activity of the transcription factor E2F1 induced by EGF was enhanced by DPP4, thus increasing PIN1 expression. Furthermore, DPP4 enhanced MEK/ERK and JNK/c-Jun signalling induced by EGF, inducing AP-1 activity and epithelial cell transformation. In contrast, DPP4 silencing or DPP4 inhibition in MCF7 cells inhibited PIN1 expression via E2F1 activity induced by EGF, decreasing colony formation and inducing DNA fragmentation. In the syngeneic 4T1 metastatic breast cancer model, DPP4 overexpression increased tumour development, whereas treatment with sitagliptin and/or juglone suppressed it. Consistent with these observations, DPP4 levels were positively correlated with PIN1 expression in human breast cancer. CONCLUSIONS AND IMPLICATIONS:DPP4 promoted EGF-induced epithelial cell transformation and mammary tumourigenesis via induction of PIN1 expression, suggesting that sitagliptin targeting of DPP4 could be a treatment strategy in patients with breast cancer.

SUBMITTER: Choi HJ

PROVIDER: S-EPMC4687806 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression.

Choi H J HJ Kim J Y JY Lim S-C SC Kim G G Yun H J HJ Choi H S HS

British journal of pharmacology 20151016 21

<h4>Background and purpose</h4>Dipeptidyl peptidase 4 (DPP4) is an aminopeptidase that is widely expressed in different cell types. Recent studies suggested that DPP4 plays an important role in tumour progression in several human malignancies. Here we have examined the mechanisms by which up-regulation of DPP4 expression causes epithelial transformation and mammary tumourigenesis.<h4>Experimental approach</h4>Expression of DPP4 and the peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (PIN1 ...[more]

PMID: 26267432

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Project description:In recent years, the biological sciences have seen a surge in the development of methods, including high-throughput global methods, for the quantitative measurement of biomolecule levels (i.e., RNA, proteins, metabolites) from cells and tissues. Just as important as quantitation of biomolecules has been the creation of approaches that uncover the regulatory and signaling connections between biomolecules. Our specific interest is in understanding peptide metabolism in a physiological setting, and this has led us to develop a multidisciplinary approach that integrates genetics, analytical chemistry, synthetic chemistry, biochemistry, and chemical biology to identify the substrates of peptidases in vivo. To accomplish this we utilize a liquid chromatography-mass spectrometry (LC-MS)-based peptidomics platform to measure changes in the peptidome as a function of peptidase activity. Previous analysis of mice lacking the enzyme dipeptidyl peptidase 4 (DPP4(-/-) mice), a biomedically relevant peptidase, using this approach identified a handful of novel endogenous DPP4 substrates. Here, we utilize these substrates and tissues from DPP4(-/-) mice to improve the coverage of the peptidomics platform by optimizing the key steps in the workflow, and in doing so, discover over 70 renal DPP4 substrates (up from 7 at the beginning of our optimization), a 10-fold improvement in our coverage. The sequences of these DPP4 peptide substrates support a broad role for DPP4 in proline-containing peptide catabolism and strengthen a biochemical model that interlinks aminopeptidase and DPP4 activities. Moreover, the improved peptidome coverage also led to the detection of greater numbers of known bioactive peptides (e.g., peptide hormones) during the analysis of gut samples, suggesting additional uses for this optimized workflow. Together these results strengthen our ability to identify endogenous peptide substrates through improved peptidome coverage and demonstrate a broader potential of this peptidomics platform.

Dataset Information

Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression.

Publications

Dipeptidyl peptidase 4 promotes epithelial cell transformation and breast tumourigenesis via induction of PIN1 gene expression.

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