LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice

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Li, Rong, Doherty, Judy, Antonipillai, Juliana, Chen, Sheng, Devlin, Mark, Visser, Kathryn, Baell, Jonathan, Street, Ian, Anderson, Robin L and Bernard, Ora (2012) LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice. Clinical and Experimental Metastasis, 30 (4). pp. 483-495. ISSN 0262-0898 (print) 1573-7276 (online)

Abstract

Metastasis is the major cause of morbidity and mortality in cancer patients. An understanding of the genes that regulate metastasis and development of therapies to target these genes is needed urgently. Since members of the LIM kinase (LIMK) family are key regulators of the actin cytoskeleton and are involved in cell motility and invasion, LIMK is considered to be a good therapeutic target for metastatic disease. Here we investigated the consequences of LIMK inhibition on growth and metastasis of human and mouse mammary tumors. LIMK activity was reduced in tumor cells by expression of dominant-negative LIMK1, by RNA interference or with a selective LIMK inhibitor. The extent of phosphorylation of the LIMK substrate, cofilin, of proliferation and invasion in 2D and 3D culture and of tumor growth and metastasis in mice were assessed. Inhibition of LIMK activity efficiently reduced the pro-invasive properties of tumor cells in vitro. Tumors expressing dominant-negative LIMK1 grew more slowly and were less metastatic in mice. However, systemic administration of a LIMK inhibitor did not reduce either primary tumor growth or spontaneous metastasis. Surprisingly, metastasis to the liver was increased after administration of the inhibitor. These data raise a concern about the use of systemic LIMK inhibitors for the treatment of metastatic breast cancer.

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Item type Article
URI https://vuir.vu.edu.au/id/eprint/22450
DOI https://doi.org/10.1007/s10585-012-9553-6
Official URL http://link.springer.com/article/10.1007%2Fs10585-...
Subjects Historical > FOR Classification > 0304 Medicinal and Bimolecular Chemistry
Current > Division/Research > College of Health and Biomedicine
Keywords ResPubID26449, LIM kinase, inhibitors, breast cancer, metastasis, actin cytoskeleton, therapy
Citations in Scopus 33 - View on Scopus
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