The effect of the broad-spectrum
anticancer agent,
cisplatin, on the expression of
DNA ligase I in human
pancreatic carcinoma MiaPaCa cells was examined in this study, since
DNA ligase I is known to be involved in various DNA repair pathways. Upon exposure of MiaPaCa cells to
cisplatin at near IC(50) value (2.5-5 microM), about 2-3-fold increase of
DNA ligase I levels was observed within 24h, while levels of other
DNA ligases (III and IV) remained unchanged or slightly decreased. The same fold-increase in
DNA ligase I levels was also observed in MiaPaCa cells exposed to
cytostatic concentrations, but not cytotoxic concentrations of
cisplatin, which significantly reduced the number of cells. Flow cytometric analysis revealed that normal cell cycle progression was disrupted in the cells treated with
cisplatin, resulting in an initial arrest of the cells in the S-phase, concomitant with a decrease of cells in G0/G1-phase. With time elapsing, the transition from S- to G2 + M-phase was observed, but further progression into G0/G1-phase was blocked. Overall, the increase of
DNA ligase I expression seems to correlate well with the arrest of the cell cycle between the S- and G2-phases in response to
cisplatin treatment. Interestingly, the
cisplatin-induced
DNA ligase I increase was abrogated by
caffeine treatment in MiaPaCa cells, suggesting that
caffeine sensitive
kinases might be important mediators in the pathway, leading to the increase of
DNA ligase I levels in response to
cisplatin. We propose that the increase of
DNA ligase I expression after exposure to
cisplatin might be required for aiding the cells to recover from the damage by facilitating the repair process.