title: LIM kinase inhibition reduces breast cancer growth and invasiveness but systemic inhibition does not reduce metastasis in mice.
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.
authors.affiliation: St Vincent's Institute of Medical Research, 9 Princes St. Fitzroy, Melbourne 3065, Australia.
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Judy
authors.initials: J
authors.lastname: Doherty
authors.forename: Juliana
authors.initials: J
authors.lastname: Antonipillai
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.forename: Mark
authors.initials: M
authors.lastname: Devlin
authors.forename: Kathryn
authors.initials: K
authors.lastname: Visser
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baell
authors.forename: Ian
authors.initials: I
authors.lastname: Street
authors.forename: Robin L
authors.initials: RL
authors.lastname: Anderson
authors.forename: Ora
authors.initials: O
authors.lastname: Bernard
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007124:Immunoenzyme Techniques; D054461:Lim Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; C515892:LIMK1 protein, human; C102895:LIMK2 protein, human; D054461:Lim Kinases