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

Rong Li, Judy Doherty, Juliana Antonipillai, Sheng Chen, Mark G Devlin, Kathryn Visser, Jonathan Bayldon Baell, Ian Philip Street, Robin Anderson, Ora Bernard

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)483 - 495
Number of pages13
JournalClinical and Experimental Metastasis
Volume30
Issue number4
DOIs
Publication statusPublished - 2013
Externally publishedYes

Cite this

Li, Rong ; Doherty, Judy ; Antonipillai, Juliana ; Chen, Sheng ; Devlin, Mark G ; Visser, Kathryn ; Baell, Jonathan Bayldon ; Street, Ian Philip ; Anderson, Robin ; Bernard, Ora. / LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice. In: Clinical and Experimental Metastasis. 2013 ; Vol. 30, No. 4. pp. 483 - 495.
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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.",
author = "Rong Li and Judy Doherty and Juliana Antonipillai and Sheng Chen and Devlin, {Mark G} and Kathryn Visser and Baell, {Jonathan Bayldon} and Street, {Ian Philip} and Robin Anderson and Ora Bernard",
year = "2013",
doi = "10.1007/s10585-012-9553-6",
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Li, R, Doherty, J, Antonipillai, J, Chen, S, Devlin, MG, Visser, K, Baell, JB, Street, IP, Anderson, R & Bernard, O 2013, 'LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice' Clinical and Experimental Metastasis, vol. 30, no. 4, pp. 483 - 495. https://doi.org/10.1007/s10585-012-9553-6

LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice. / Li, Rong; Doherty, Judy; Antonipillai, Juliana; Chen, Sheng; Devlin, Mark G; Visser, Kathryn; Baell, Jonathan Bayldon; Street, Ian Philip; Anderson, Robin; Bernard, Ora.

In: Clinical and Experimental Metastasis, Vol. 30, No. 4, 2013, p. 483 - 495.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice

AU - Li, Rong

AU - Doherty, Judy

AU - Antonipillai, Juliana

AU - Chen, Sheng

AU - Devlin, Mark G

AU - Visser, Kathryn

AU - Baell, Jonathan Bayldon

AU - Street, Ian Philip

AU - Anderson, Robin

AU - Bernard, Ora

PY - 2013

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N2 - 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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