Depsipeptide a histone deacetlyase inhibitor down regulates levels of matrix metalloproteinases 2 and 9 mRNA and protein expressions in lung cancer cells (A549).
BACKGROUND
A novel histone deacetylase inhibitor, depsipeptide FR901228 (FK228), is a promising anticancer and antiproliferative agent and has been proposed to regulate gene transcription and reported to lower the risk of several cancers in different cell lines. Depsipeptide showed therapeutic efficacy in Phase I trial of patients with malignant lymphoma. Based on the recognition that basement membrane disruption occurs in acute lung injury and that matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) can degrade type IV collagen, one of the major components of the basement membrane and known to involve in tumor invasion and metastases. We hypothesized that depsipeptide would modulate MMP-2 and MMP-9 production in lung adenocarcinoma cells line (A549).


METHODS
In this study, we observed the precise involvement of depsipeptide role on cancer metastasis. A549 cells were treated with depsipeptide at various concentrations (50 and 100nm), for 24h period and then subjected to mRNA levels with RT-PCR and protein levels with Western blot analysis to investigate the impact of depsipeptide on MMP-2 and MMP-9 expressions and further confirmed by using immunocytochemistry.


RESULTS
The results showed that depsipeptide treatment decreased the expressions of MMP-2 and MMP-9 in dose-dependent manner. The level of mRNA and proteins expressions were significantly decreased in depsipeptide treated A549 cells in a dose-dependent manner and the level of pro-MMP-9 was found to be high in the 100nm depsipeptide-treated cell lysate of A549 cells, suggesting inhibitory role of depsipeptide on pro-MMP-9 activation. Further immunocytochemistry studies showed the weak expression of MMP-2 and MMP-9 in depsipeptide treated cells.


CONCLUSIONS
We speculate that inhibition of metastasis-specific MMPs in cancer cells may be one of the targets for anticancer function of depsipeptide, and thus provides the molecular basis for the development of depsipeptide as a novel chemopreventive agent for metastatic lung cancer.
Vinodhkumar
Radhakrishnan
R
Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, India.
Song
Young-Sun
YS
Ravikumar
Vilwanathan
V
Ramakrishnan
Gopalakrishnan
G
Devaki
Thiruvengadem
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D012333:RNA, Messenger / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; C087123:romidepsin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9