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


METHODS
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.


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
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.
College of Pharmacy, Chosun University, Gwangju, South Korea.
H J
HJ
Choi
College of Pharmacy, Chosun University, Gwangju, South Korea.
J Y
JY
Kim
Department of Pathology, School of Medicine, Chosun University, Gwangju, South Korea.
S-C
SC
Lim
College of Pharmacy, Chosun University, Gwangju, South Korea.
G
G
Kim
College of Pharmacy, Chosun University, Gwangju, South Korea.
H J
HJ
Yun
College of Pharmacy, Chosun University, Gwangju, South Korea.
H S
HS
Choi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics*; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D000068900:Sitagliptin Phosphate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000096:biosynthesis; D015854:Up-Regulation
D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D018808:Transcription Factor AP-1; D019938:Cyclin D1; D004815:Epidermal Growth Factor; D011494:Protein Kinases; D018819:Dipeptidyl Peptidase 4; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D000068900:Sitagliptin Phosphate