Suppression of neuroblastoma growth by dipeptidyl peptidase IV: relevance of chemokine regulation and caspase activation

Arscott, W. Tristram; LaBauve, Annette E.; May, Víctor; Wesley, Umadevi V.

doi:10.1038/onc.2008.402

Cited by 55 publications

(57 citation statements)

References 62 publications

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“…Complementary DNA (cDNA) was synthesized from 5 µg of total RNA using 0.5 µg of Oligo(dT) 15 -primer (Roche Diagnostics) and SuperScript ® III Reverse Transcriptase (Invitrogen) as per the manufacturer's instructions. Quantitative measurements of DPs and PEP mRNA levels were determined by real-time qPCR using TaqMan™ probe technology and external PCR product standards of known copy number.…”

Section: Rna Isolation and Real-time Quantitative Pcr (Qpcr)mentioning

confidence: 99%

“…Notably, the chemokine CXC12 [stromal derived factor 1 (SDF-1)], a known endogenous DP4 substrate (9) which is also cleaved by DP8 in vitro (7) and its receptor, CXCR4, form a CXC12/CXCR4 axis that appears to play an important role in tumor cell proliferation and metastases of numerous cancers including breast and epithelial ovarian cancer (10-12). DP4 proteolysis inactivates SDF-1α/β, disrupting the SDF-1/ CXCR4 interaction affecting downstream signaling and the likely SDF-1 mediated cell migration and metastasis (13)(14)(15) …”

Section: Introductionmentioning

confidence: 99%

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

Wilson

Abbott

2012

International Journal of Oncology

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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...

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Section: Rna Isolation and Real-time Quantitative Pcr (Qpcr)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wilson

Abbott

2012

International Journal of Oncology

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“…In the Burkitt's B-cell lymphoma line DPP4 overexpression results in elevated p38 mitogen-activated protein kinases [MAPK; extracellular signal regulated kinase (ERK1/2)] phosphorylation (18). Using the nonselective DPP inhibitor Diprotin A, Arscott and colleagues showed that DPP4 enzyme activity downregulates fetal calf serum (FCS) stimulated Akt phosphorylation in the neuroblastoma cell line, SK-N-AS (2). However, an important remaining question is whether DPP4 could function as a cytoplasmic signaling enzyme in addition to its extracellular dipeptidyl peptidase activity.…”

Section: Introductionmentioning

confidence: 99%

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

Yao

Kim

et al. 2011

Molecular Cancer Research

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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.

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“…Indeed, the kidney is where DPP-4 is expressed at the highest level per organ weight (13). Interestingly, DPP-4 has been associated with cell survival signaling and extracellular matrix remodelings (14)(15)(16).…”

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confidence: 99%

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

et al. 2014

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Kidney fibrosis is the final common pathway of all progressive chronic kidney diseases, of which diabetic nephropathy is the leading cause. Endothelial-to-mesenchymal transition (EndMT) has emerged as one of the most important origins of matrix-producing fibroblasts. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been introduced into the market as antidiabetes drugs. Here, we found that the DPP-4 inhibitor linagliptin ameliorated kidney fibrosis in diabetic mice without altering the blood glucose levels associated with the inhibition of EndMT and the restoration of microRNA 29s. Streptozotocin-induced diabetic CD-1 mice exhibited kidney fibrosis and strong immunoreactivity for DPP-4 by 24 weeks after the onset of diabetes. At 20 weeks after the onset of diabetes, mice were treated with linagliptin for 4 weeks. Linagliptin-treated diabetic mice exhibited a suppression of DPP-4 activity/protein expression and an amelioration of kidney fibrosis associated with the inhibition of EndMT. The therapeutic effects of linagliptin on diabetic kidneys were associated with the suppression of profibrotic programs, as assessed by mRNA microarray analysis. We found that the induction of DPP-4 observed in diabetic kidneys may be associated with suppressed levels of microRNA 29s in diabetic mice; linagliptin restored microRNA 29s and suppressed DPP-4 protein levels. Using cultured endothelial cells, we found that linagliptin inhibited TGF-β2–induced EndMT, and such anti-EndMT effects of linagliptin were mediated through microRNA 29 induction. These results indicate the possible novel pleiotropic action of linagliptin to restore normal kidney function in diabetic patients with renal impairment.

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Suppression of neuroblastoma growth by dipeptidyl peptidase IV: relevance of chemokine regulation and caspase activation

Cited by 55 publications

References 62 publications

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

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

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

Linagliptin-Mediated DPP-4 Inhibition Ameliorates Kidney Fibrosis in Streptozotocin-Induced Diabetic Mice by Inhibiting Endothelial-to-Mesenchymal Transition in a Therapeutic Regimen

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