Control of cell cycle progression in human mesothelioma cells treated withgamma interferon

Recombinant human interferon gamma (r-hu-IFN gamma) exerts both antitumoral activity in the early stages of human malignant mesothelioma and a cytosta tic effect in human mesothelioma (HM) cell lines in vitro. The antiprolifer ative effect of interferons (IFNs) reported in a variety of cells has been attributed to several mechanisms. In order to progress in the understanding of HM cell growth modulation by r-hu-IFN gamma, modifications of cell cycl e progression and expression of key cell cycle regulator proteins in respon se to r-hu-IFN gamma were examined. Nine HM cell lines were studied, includ ing one resistant to the antiproliferative effect of r-hu-IFN gamma. Except in the resistant cell line r-hu-IFN gamma produced an arrest in the G1 and G2-M phases of the cell cycle, associated with a reduction in both cyclin A and cyclin dependent kinase inhibitors (CDKIs) expression. Moreover cycli n B1/cdc2 activity was decreased. The present study provides the first evid ence of a GZ-arrest in r-hu-IFN gamma -treated HM cell lines and indicates that HM cell lines, despite their tumorigenic origin still support cell cyc le control. The cell cycle arrest induced by r-hu-IFN gamma seems to depend on cyclin regulation through p21(WAF1/C1P1)- and p27(KiP1)-independent mec hanisms and is not directly related to the induced DNA damage.