Anti cancer properties of natural compounds downregulating UHRF1 in CASKI cells

Abstract

Cervical cancer is a leading cause of cancer mortality in women. Disruption of epigenetic machinery due to UHRF1 overexpression promotes carcinogenesis. In this study, silencing of UHRF1 induced cell cycle arrest and apoptosis in CaSki cells. Network pharmacology revealed the potential of ellagic acid, plumbagin and salicylic acid to target proliferation, apoptosis and migration related pathways in cervical cancer. At their IC50 values, ellagic acid (140 and#956;M), plumbagin (4 and#956;M) and salicylic acid (150 and#956;M) downregulated UHRF1 in CaSki cells and reduced their colony forming potential. CaSki cells were arrested at G0-G1 by ellagic acid, salicylic acid and G2-M phase by plumbagin. These compounds upregulated p21, miR-202-5p and downregulated E2F1. There was loss of mitochondrial membrane potential and induction of apoptosis. Mechanistically, pAkt and full-length PARP were downregulated whereas cleaved forms of caspase 9 and caspase 3 were upregulated after the treatment. These compounds also inhibited migration of CaSki cells. Ellagic acid and plumbagin reduced UHRF1 enrichment on the promoter of E-cadherin, the cell adhesion marker and PAX1, the anti-metastasis marker which resulted in their upregulation, respectively. PAX1 promoter revealed partial reversal of hypermethylation and enrichment of H2BK12ac and H2AK5ac after plumbagin treatment. The expression and activity of matrix metalloproteinase 2 (MMP-2) was reduced with concomitant upregulation of its endogenous inhibitor TIMP-2 after the treatment with plumbagin. Ellagic acid, plumbagin and salicylic acid synergistically reduced the effective concentration of cisplatin by 1.98, 13.23 and 8.10 fold, respectively and augmented apoptosis in CaSki cells. Based on these findings, ellagic acid, plumbagin and salicylic acid could be considered as lead natural compounds for in vivo studies to validate their anti-cancer activity against cervical cancer. newline