A Novel Role of Dipeptidyl Peptidase 9 in Epidermal Growth Factor Signaling

Abstract

Dipeptidyl peptidase IV (DPP4), DPP8, DPP9, and fibroblast activation protein (FAP), the four proteases of the DPP4 gene family, have unique peptidase and extra-enzymatic activities that have been implicated in various diseases including cancers. We report here a novel role of DPP9 in regulating cell survival and proliferation through modulating molecular signaling cascades. Akt (protein kinase B) activation was significantly inhibited by human DPP9 overexpression in human hepatoma cells (HepG2 and Huh7) and human embryonic kidney cells (HEK293T), whereas extracellular signal-regulated kinases (ERK1/2) activity was unaffected, revealing a pathwayspecific effect. Interestingly, the inhibitory effect of DPP9 on Akt pathway activation was growth factor dependent. DPP9 overexpression caused apoptosis and significantly less epidermal growth factor (EGF)-mediated Akt activation in HepG2 cells. However, such inhibitory effect was not observed in cells stimulated with other growth factors, including connective tissue growth factor, hepatic growth factor, insulin or platelet-derived growth factor-BB. The effect of DPP9 on Akt did not occur when DPP9 enzyme activity was ablated by either mutagenesis or inhibition. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a major downstream effector of Ras. We found that DPP9 and DPP8, but not DPP4 or FAP, associate with H-Ras, a key signal molecule of the EGF receptor signaling pathway. These findings suggest an important signaling role of DPP9 in the regulation of survival and proliferation pathways. Mol Cancer Res; 9(7); 948-59. Ó2011 AACR.

Expression profiling of dipeptidyl peptidase 8 and 9 in breast and ovarian carcinoma cell lines

“…In all cell lines analyzed in our study, we observed no correlation between the endogenous expression of DP8 and DP9 mRNA and protein. This is consistent with the Yao et al observation of no change in DP8 protein expression following heterologous overexpression of DP9 in HEK293T and HepG2 cells (36).…”

“…However, information on the expression of DP8 and DP9 in pathophysiological settings and potential roles in cancer is limited. In contrast to the recently identified NPY-dependent survival role suggested for DP8/DP9 in Ewings sarcoma (16), the overexpression of DP8 and DP9 in HEK293T and HepG2 cells has been shown to increase migration, proliferation and enhance staurosporine-streptomyces induced apoptosis (17,36) suggesting the effects of DP8/DP9 in cancer, like DP4 and FAP, may be tumor specific. In chronic lymphocytic leukemia (CLL) a significant increase in DP8 mRNA has been observed (37) while upregulation of DP9 mRNA has been observed in testicular cancer (38).…”

“…Recent data suggest that high levels of endogenous DP4, DP8 and DP9 can provide a survival mechanism for ESFT, protecting ESFT cells from endogenous NPY-induced cell death (16) while heterologous overexpression of DP8 and DP9 has been shown to enhance staurosporine-induced apoptosis and spontaneous apoptosis in the case of DP9 (17,36). These differences highlight the importance of investigating endogenous expression of DPs in the context of differing pathological settings.…”

“…Yao et al showed that DP9 overexpression inactivated phosphoinositide 3-kinase (PI3K)/Akt signaling in an epidermal growth factor (EGF)-dependent manner, attenuating cell proliferation and enhancing apoptosis (36). Akt is a key activator of cell growth and survival mechanisms (72).…”

Contribution of upregulated dipeptidyl peptidase 9 (DPP9) in promoting tumoregenicity, metastasis and the prediction of poor prognosis in non‐small cell lung cancer (NSCLC)

“…Additionally, the inhibition of intracellular DPP9 enhances the anti‐leukemic activity of parthenolide,28 while DPP9 may also act as a survival factor for cells from the Ewing's sarcoma family of tumors cells and protect them against cell death induced by endogenous neuropeptide Y 29. On the other hand, DPP9 overexpression was reported to inhibit phosphoinositide 3‐kinase/Akt signaling in an epidermal growth factor receptor‐dependent manner, attenuating cell proliferation and promoting apoptosis in human hepatoma cells 30. Therefore, the pro‐ or anti‐tumor activity of DPP9 may depend on the cell type and the molecular context within the tumor microenvironment.…”