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

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Abstract

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.

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Abbreviations

PCa:

Prostate cancer

DDAH1:

Dimethylarginine dimethylaminohydrolase-1

ADMA:

Asymmetric dimethylarginine

NO:

Nitric oxide

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Acknowledgements

This work is supported by SMILE (CSC-0111) project supported by Council for Scientific and Industrial Research (CSIR) under 12th five-year plan during 2012 to 2017. KKR acknowledge UGC for CSIR-UGC fellowship for graduate students.

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Authors and Affiliations

  1. Center for Chemical Biology, CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Tarnaka, Uppal Road, Hyderabad, 007, India

    Karthik Reddy Kami Reddy, Chandrashekhar Dasari, Divya Duscharla, Bhukya Supriya & Ramesh Ummanni

  2. Center for Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Hyderabad, India

    Karthik Reddy Kami Reddy, Chandrashekhar Dasari, Divya Duscharla & Ramesh Ummanni

  3. Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India

    N. Sai Ram & Jerald Mahesh Kumar

  4. National Institute of Nutrition (NIN), Hyderabad, India

    M. V. Surekha

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Reddy, K.R.K., Dasari, C., Duscharla, D. et al. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is frequently upregulated in prostate cancer, and its overexpression conveys tumor growth and angiogenesis by metabolizing asymmetric dimethylarginine (ADMA). Angiogenesis 21, 79–94 (2018). https://doi.org/10.1007/s10456-017-9587-0

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