Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer.
BACKGROUND
LIM kinase 1 (LIMK1), a LIM domain containing serine/threonine kinase, modulates actin dynamics through inactivation of the actin depolymerizing protein cofilin. Recent studies have indicated an important role of LIMK1 in growth and invasion of prostate and breast cancer cells; however, the molecular mechanism whereby LIMK1 induces tumor progression is unknown. In this study, we investigated the effects of ectopic expression of LIMK1 on cellular morphology, cell cycle progression and expression profile of LIMK1 in prostate tumors.


RESULTS
Ectopic expression of LIMK1 in benign prostatic hyperplasia cells (BPH), which naturally express low levels of LIMK1, resulted in appearance of abnormal mitotic spindles, multiple centrosomes and smaller chromosomal masses. Furthermore, a transient G1/S phase arrest and delayed G2/M progression was observed in BPH cells expressing LIMK1. When treated with chemotherapeutic agent Taxol, no metaphase arrest was noted in these cells. We have also noted increased nuclear staining of LIMK1 in tumors with higher Gleason Scores and incidence of metastasis.


CONCLUSIONS
Our results show that increased expression of LIMK1 results in chromosomal abnormalities, aberrant cell cycle progression and alteration of normal cellular response to microtubule stabilizing agent Taxol; and that LIMK1 expression may be associated with cancerous phenotype of the prostate.
Davila
Monica
M
Department of Molecular biology and Microbiology, University of Central Florida, Orlando, Florida, USA. monica.davila@flhosp.org
Jhala
Darshana
D
Ghosh
Debashis
D
Grizzle
William E
WE
Chakrabarti
Ratna
R
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D043171:Chromosomal Instability; D005455:Fluorescent Antibody Technique; D016193:G1 Phase; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D054461:Lim Kinases; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology; D011230:Precancerous Conditions / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis*; D016196:S Phase; D046888:Tissue Array Analysis
D000972:Antineoplastic Agents, Phytogenic; D011494:Protein Kinases; C515892:LIMK1 protein, human; D054461:Lim Kinases; D017239:Paclitaxel