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Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94

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Abstract

A significant proportion of breast cancer patients harbor clinically undetectable micrometastases at the time of diagnosis. If left untreated, these micro-metastases may lead to disease relapse and possibly death. Hence, there is significant interest in the development of novel anti-metastatic agents that could also curb the growth of pre-established micrometastases. Like primary tumor, the growth of metastases also is driven by angiogenesis. Although the role of cysteine protease Cathepsin L (CTSL) in metastasis associated tumor cell functions such as migration and invasion is well recognized, its role in tumor angiogenesis remains less explored. The present study examines the contribution of CTSL to breast cancer angiogenesis and evaluates the anti-angiogenic efficacy of CTSL inhibitor KGP94. CTSL semi-quantitative RT-PCR analysis on breast tissue panels revealed significant upregulation of CTSL in breast cancer patients which strongly correlated with increased relapse and metastatic incidence and poor overall survival. Preclinically, CTSL ablation using shRNA or KGP94 treatment led to a significant reduction in MDA-MB-231 tumor cell induced angiogenesis in vivo. In-vitro assessments demonstrated a significant decrease in various angiogenic properties such as endothelial cell sprouting, migration, invasion, tube formation and proliferation in the presence of KGP94. Microarray analyses revealed a significant upregulation of cell cycle related genes by CTSL. Western blot analyses further confirmed upregulation of members of the cyclin family by CTSL. Collectively, these data indicate that CTSL is an important contributor to tumor angiogenesis and that the CTSL inhibition may have therapeutic utility in the treatment of breast cancer patients.

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Acknowledgments

The authors thank Dr. Kevin Pinney of Baylor University and OXiGENE Inc. for providing KGP94. These studies were supported in part by a grant from the National Cancer Institute (US Public Health Service Grant R01 CA169300).

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Florida Health Cancer Center, Gainesville, USA

    Dhivya R. Sudhan & Dietmar W. Siemann

  2. Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, USA

    Dietmar W. Siemann

  3. Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, USA

    Charles E. Wood

  4. CEPROCOR, National Scientific and Technical Research Council (CONICET), Córdoba, Argentina

    Maria B. Rabaglino

  5. Cancer and Genetics Research Complex, University of Florida Health Cancer Center, Room 485E, Gainesville, FL, 32610, USA

    Dhivya R. Sudhan

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  1. Dhivya R. Sudhan
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  2. Maria B. Rabaglino
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Correspondence to Dhivya R. Sudhan.

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Sudhan, D.R., Rabaglino, M.B., Wood, C.E. et al. Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94. Clin Exp Metastasis 33, 461–473 (2016). https://doi.org/10.1007/s10585-016-9790-1

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  • DOI: https://doi.org/10.1007/s10585-016-9790-1

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