Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is frequently upregulated in prostate cancer, and its overexpression conveys tumor growth and angiogenesis by metabolizing asymmetric dimethylarginine (ADMA)

Autor: Jerald Mahesh Kumar, M V Surekha, Karthik Reddy Kami Reddy, Chandrashekhar Dasari, Bhukya Supriya, Divya Duscharla, N Sai Ram, Ramesh Ummanni
Rok vydání: 2017
Předmět:
0301 basic medicine
CD31
Male
Vascular Endothelial Growth Factor A
Cancer Research
Physiology
Angiogenesis
Clinical Biochemistry
Mice
Nude
Nitric Oxide Synthase Type II
Arginine
Nitric Oxide
Nitric oxide
Amidohydrolases
03 medical and health sciences
chemistry.chemical_compound
Prostate cancer
Mice
0302 clinical medicine
Cell Movement
LNCaP
medicine
Animals
Humans
Neoplasm Invasiveness
Cell Proliferation
Neovascularization
Pathologic
Chemistry
Cell growth
Interleukin-8
Prostatic Neoplasms
medicine.disease
Hypoxia-Inducible Factor 1
alpha Subunit
Neoplasm Proteins
Up-Regulation
Gene Expression Regulation
Neoplastic
Platelet Endothelial Cell Adhesion Molecule-1
030104 developmental biology
Cell culture
030220 oncology & carcinogenesis
PC-3 Cells
Cancer research
Heterografts
Fibroblast Growth Factor 2
Asymmetric dimethylarginine
Neoplasm Transplantation
Signal Transduction
Zdroj: Angiogenesis. 21(1)
ISSN: 1573-7209
Popis: Tissue microarray analysis confirmed higher dimethylarginine dimethylaminohydrolase-1 (DDAH1) expression in prostate cancer (PCa) compared to benign and normal prostate tissues. DDAH1 regulates nitric oxide (NO) production by degrading endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA). This study examined whether DDAH1 has any physiological role in PCa progression. Using overexpression of DDAH1 in PCa (PC3 and LNCaP) cell lines, we found that DDAH1 promotes cell proliferation, migration and invasion by lowering ADMA levels, as well as increasing NO production. VEGF, HIF-1α and iNOS were upregulated in DDAH1 expressing cells as result of elevated NO. DDAH1 increased secretion of pro-angiogenic signals bFGF and IL-8, into conditioned media. Treatment of DDAH1-positive PCa cells with NOS inhibitors (L-NAME and 1400 W) attenuated DDAH1 activity to promote cell growth. Xenografts derived from these cells grew significantly faster (> twofold) than those derived from control cells. Proliferation rate of cells stably expressing mutant DDAH1 was same as control cells unlike wild-type DDAH1-positive PCa cells. Xenograft tumors derived from mutant-positive cells did not differ from control tumors. VEGF, HIF-1α and iNOS expression did not differ in DDAH1 mutant-positive tumors compared to control tumors, but was upregulated in wild-type DDAH1 overexpressing tumors. Furthermore, CD31 immunostaining on xenograft tissues demonstrated that DDAH1 tumors had high endothelial content than mutant DDAH1 tumors. These data suggest that DDAH1 is an important mediator of PCa progression and NO/DDAH pathway needs to be considered in developing therapeutic strategies targeted at PCa.
Databáze: OpenAIRE
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