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Inhibitory effect of cathepsin K inhibitor (ODN-MK-0822) on invasion, migration and adhesion of human breast cancer cells in vitro

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Abstract

Approximately 90% of patients with advanced breast cancer develop bone metastases; an event that results in severe decrease of quality of life and a drastic deterioration in prognosis. Therefore, to increase the survival of breast cancer patients, the development of new therapeutic strategies to impair metastatic process and skeletal complications is critical. Previous studies on the role of cathepsin K (CTSK) in metastatic spreading led to several strategies for inhibition of this molecule such as MIV-711 (Medivir), balicatib and odanacatib (ODN) which were on trial in the past. The present study intended to assess the anti-metastatic efficacy of ODN in breast cancer cells. Human breast cancer cell lines MDA-MB-231 were treated with different concentrations of ODN and performed invasion, adhesion and migration assays and, RT-PCR and western blot to evaluate the effect of ODN on the metastatic potential of breast cancer cells. ODN markedly decreased wound healing cell migration, invasion and adhesion at a dose dependent manner. ODN inhibits cell invasion by decreasing the matrix metalloproteinase (MMP-9) with the upregulation of TIMP-1 expression. ODN effectively inhibited the phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal Kinase (JNK), and blocked the expression of β-integrins and FAK proteins. ODN also significantly inhibited PI3K downstream targets Rac1, Cdc42, paxillin and Src which are critical for cell adhesion, migration and cytoskeletal reorganization. ODN exerts anti-metastatic action through inhibition of signaling pathway for MMP-9, PI3K and MAPK. This indicates potential therapeutic effects of ODN in the treatment of metastatic breast cancer.

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Acknowledgements

The author is thankful to University Grants Commission (UGC), India for funding to carry out this work.

Funding

This work was financially supported by University Grants Commission (UGC) for UGC: NFST India with IF no. NFST-2015–17-ST- MAN-689.

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Authors and Affiliations

  1. Department of Biochemistry, Armed Forces Medical College, Pune, India

    Yaongamphi Vashum

  2. Department of Biochemistry, VRR Institute of Biomedical Science (Affiliated to University of Madras), Chennai, India

    Amuthavalli Kottaiswamy, Mathangi Soma, Abirami Padmanaban & Shila Samuel

  3. Department of Biochemistry and Chemical Biology, Indian Institute of Science Education & Research (IISER), Pune, India

    Riya Premsingh

  4. Department of Medicine and Surgery, Chettinad Hospital and Research Institute, Chennai, India

    Parkavi Kalaiselvan

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Vashum, Y., Premsingh, R., Kottaiswamy, A. et al. Inhibitory effect of cathepsin K inhibitor (ODN-MK-0822) on invasion, migration and adhesion of human breast cancer cells in vitro. Mol Biol Rep 48, 105–116 (2021). https://doi.org/10.1007/s11033-020-05951-0

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