Overexpression of macrophage inhibitory cytokine-1 induces metastasis of human prostate cancer cells through the FAK-RhoA signaling pathway.
An elevated level of macrophage inhibitory cytokine-1 (MIC-1) is reported in the sera of patients with metastatic prostate cancer compared with that of benign diseases and healthy adults. We investigated the mechanistic role of MIC-1 overexpression in the metastasis of prostate cancer cells. Our study showed a progressive increase in secretory MIC-1 production correlated with the increase in the metastatic potential of PC-3 and LNPCa prostate cancer metastatic variants. Further, the in vitro studies using 'loss-' and 'gain'-of-function approaches showed that ectopic overexpression of MIC-1 (PC-3-MIC-1) and forced downregulation of MIC-1(PC-3M-siMIC-1) enhanced and reduced the motility and invasiveness of these cells, respectively. Supporting our in vitro observations, all the mice orthotopically implanted with PC-3-MIC-1 cells developed metastasis compared with none in the PC-3-vector group. Our results showed that MIC-1 overexpression was associated with apparent changes in actin organization. In addition, an enhanced phosphorylation of focal adhesion kinase (FAK) and guanosine-5'-triphosphate (GTP)-bound RhoA was also seen; however, no significant change was observed in total FAK and RhoA levels in the PC-3-MIC-1 cells. Altogether, our findings show that MIC-1 has a role in prostate cancer metastasis, in part, by promoting the motility of these cells. Activation of the FAK-RhoA signaling pathway is involved in MIC-1-mediated actin reorganization, and thus, leads to an increase in the motility of prostate cancer cells.
Senapati
S
S
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA.
Rachagani
S
S
Chaudhary
K
K
Johansson
S L
SL
Singh
R K
RK
Batra
S K
SK
D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology* / Q000503:physiopathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000502:physiology
D055436:Growth Differentiation Factor 15; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020742:rhoA GTP-Binding Protein