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

Abstract

Abstract. Proteases, particularly serine proteases like dipeptidyl peptidase 4 (DP4) and fibroblast activation protein (FAP), play an important role in cancer invasion and angiogenesis. Aberrant expression of DP4 and FAP is associated with numerous cancers, including breast and epithelial ovarian carcinoma. We investigated the mRNA levels, protein expression and enzyme activity of the structural homologs DP8 and DP9, in addition to DP4 and FAP, in three breast carcinoma (MDA-MB-231, MDA-MB-453, MCF-7), three epithelial ovarian carcinoma (EOC) (OVCA-432, OVCA-429, SKOV3), 293T and HeLa cell lines. In addition, DP2 and prolyl endopeptidase (PEP) mRNA and enzyme levels were measured and compared in each cell line. Ubiquitous but differential expression of DP8 and DP9 mRNA and protein was observed across all cell lines. Relative to EOC, DP8 protein was lower in the breast carcinoma cell lines (p= 0.057), suggesting that DP8 may play differing roles in different cancer cell types. A strong, negative, non-reciprocal relationship was identified between DP9 protein and DP4 mRNA (r=-0.903, p=0.002) and protein (r=-0.810, p=0.015). This suggests that DP4 expression plays an important role in the post-transcriptional regulation of DP9 in breast and ovarian cancer cell lines. Overall, this study suggests a potential role for DP8 and DP9 in breast and ovarian cancer and further investigations in this area are required. IntroductionBreast and ovarian cancer are two of the most common and lethal cancers affecting women worldwide. Estimates rank breast cancer as being the number one cause of new cancer cases (1,383,000 cases, 22.9%) and cancer related deaths (458,000 deaths, 13.7%) in women worldwide in 2008. Ovarian cancer was ranked as the seventh cause of new cancer cases (225,000 cases, 3.7%) and cancer related deaths (140,000 deaths, 4.2%) in women worldwide in the same year (1). Among gynecological malignancies, epithelial ovarian carcinoma (EOC) is the most lethal to women in the world, accounting for approximately 90% of all tumors affecting the ovaries (2). Mortality from breast cancer often results from distant metastatic spread to lung, bone and lymph node tissue while diagnosis of EOC typically occurs in the late stages of disease after its spread into the peritoneal cavity or other distant sites (2), thus making it difficult for effective treatment to be administered. Although a number of risk factors for the development of breast and ovarian cancer have been identified the exact origin and pathogenesis of disease is still poorly understood (3,4). Increasing our knowledge about the fundamental biology of these diseases is needed for the development of improved diagnostic, prognostic and therapeutic interventions at all stages of disease.Enzymatic members of the DP4-like gene family, DP4, FAP, DP8 and DP9, share the rare ability to cleave N-terminal dipeptides at post-proline bonds in the penultimate position and play an important role in the biological processing of the N-termini of peptides such as chemokines, glu...

Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins

“…Thus, by means of their associations and substrate specificities, the DPP4/FAP heteromeric complex is responsible for tumour invasion, migration, metastasis and angiogenesis [6,7,13,[22][23][24]. Furthermore, potential roles of DPP8 and DPP9 have been suggested in breast and ovarian cancer and an upregulation of DPP9 has been detected in testicular tumours [35,94,132]. In addition, DPP9 was found to regulate cell survival and proliferation by inhibiting Akt activation involving the EGF signalling pathway.…”

Advances in Understanding the Expression and Function of Dipeptidyl Peptidase 8 and 9

“…DPP8 mRNA expression is significantly greater than all the other DPPs in breast cancer and ovarian cancer cell lines, but DPP8 and DPP9 protein expression is ubiquitous across those cell lines (70). DPP9 mRNA is also greatly upregulated in human testicular tumors (59).…”

“…DPP9 mRNA is also greatly upregulated in human testicular tumors (59). Interestingly, the highest level of DPP9 protein is in 2 estrogen receptor negative breast cancer cell lines that are negative for DPPIV mRNA (70). In many tumor tissues, including skin melanotic melanoma, neuroblastoma, and leukemia, the long form of human DPP9 mRNA is expressed (23).…”

Identifying Natural Substrates for Dipeptidyl Peptidases 8 and 9 Using Terminal Amine Isotopic Labeling of Substrates (TAILS) Reveals in Vivo Roles in Cellular Homeostasis and Energy Metabolism

“…In cancer, increased DP8 mRNA has been found in chronic lymphocytic leukemia (12) and DP9 mRNA in testicular cancer (3), and increased levels of DP8/DP9 mRNA, protein, and enzymatic activity have been observed in human meningiomas (13). Ubiquitous but differential expression of DP8/DP9 has been observed in breast and ovarian carcinoma cell lines (14), and a study has identified DP8/DP9 as survival factors for the Ewing sarcoma family of tumors (15). Despite these findings, the mechanism(s) of DP8/DP9 function in these events has yet to be identified, and their exact biological roles remain unknown.…”