Macrophage inhibitory cytokine 1 reduces cell adhesion and induces apoptosis in prostate cancer cells.
Macrophage inhibitory cytokine 1 (MIC-1), a divergent member of the transforming growth factor-beta superfamily, is linked to the pathogenesis of cancer. To delineate possible roles for MIC-1 in prostate cancer, a number of prostate epithelial cell lines have been studied, including PZ-HPV-7, DU-145, PC-3, and LNCaP cells. Factors regulating the production of MIC-1 protein by these cells and some of the effects of MIC-1 on them were investigated. Although PZ-HPV-7 and DU-145 produced no MIC-1 protein, PC-3 and LNCaP cells secreted MIC-1 protein at high levels. The secretion of MIC-1 in LNCaP cells was modulated by both androgen and estrogen. Although neither MIC-1 nor anti-MIC-1 antibody had any effect on the proliferation of epithelial cells, MIC-1 induced changes in DU-145 cells. These cells became flattened and more spread out, and this was accompanied by reduced intercellular actin filaments and intercellular junctions. The DU-145 cells then detached from their substrate and underwent caspase-dependent apoptosis. To define some of the genes responsible for these changes, cDNA microarrays, followed by confirmatory reverse transcription-PCR, was used to analyze differential gene expression induced by MIC-1. The antiapoptotic gene metallothionein 1E and cell adhesion genes RhoE and catenin delta 1 were down-regulated by more than 2-fold by MIC-1, suggesting that they were, at least in part, responsible for the observed changes in the behavior of DU-145 cells. These findings suggest that although MIC-1 has no effect on cell proliferation, it reduces cell adhesion and consequently induces cell detachment. It is likely that caspase-dependent apoptosis is secondary to loss of cell adhesion and may suggest a role for MIC-1 in tumor dissemination in vivo.
Liu
Tao
T
Centre for Immunology, St. Vincent's Hospital and University of New South Wales, Victoria Street, Sydney, NSW 2010, Australia.
Bauskin
Asne R
AR
Zaunders
John
J
Brown
David A
DA
Pankhurst
Susan
S
Russell
Pamela J
PJ
Breit
Samuel N
SN
Panhurst
Susan
S
D017209:Apoptosis; D020169:Caspases / Q000502:physiology; D002448:Cell Adhesion; D002455:Cell Division; D016207:Cytokines / Q000502:physiology*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D020869:Gene Expression Profiling; D055436:Growth Differentiation Factor 15; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D014407:Tumor Cells, Cultured
D016207:Cytokines; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D016212:Transforming Growth Factor beta; D013196:Dihydrotestosterone; D004958:Estradiol; D020169:Caspases