Ukrain Affects Pancreas Cancer Cell Phenotype in vitro by Targeting MMP-9 and Intra-/Extracellular SPARC Expression

Background/Aims: We investigated whether the anticancer drug Ukrain (UK) is able to modulate the expression of some of the key markers of tumor progression in pancreatic cell carcinoma, in order to assess its potential therapeutic effect. Methods: Three cell lines (HPAF-II, PL45,HPAC) were treated with UK (5,10 and 20 μM) for 48 h, or left untreated. Secreted protein acidic and rich in cysteine (SPARC) mRNA levels were assessed by real-time PCR. Matrix metalloproteinases (MMP)-2 and -9 activity was analyzed by SDS zymography; SPARC protein levels in cell lysates and supernatants were determined by Western blot. Cell cycle was determined by flow cytometric analysis, and invasion by matrigel invasion assay. Results: UK down-regulated MMP-2 and MMP-9, suggesting that UK may decrease pancreatic cancer cell invasion, as confirmed by the matrigel invasion assay. SPARC protein down-regulation in supernatants points to an inhibition by UK of extracellular matrix remodeling in the tumor microenvironment. At the same time, SPARC mRNA and cellular protein level up-regulation suggests that UKcan affect cell proliferation by cell cycle inhibition, showing a cell cycle G2/M arrest in UK-treated cells. Conclusion: Our results suggest that UK modulates two major aspects involved in tumorigenesis of pancreatic cancer cells, such as extracellular matrix remodeling and cell proliferation.