Interferon-beta induces S phase slowing via up-regulated expression of PMLin squamous carcinoma cells

Type I Interferon (IFN) and all-trans retinoic acid (RA) inhibit cell proli feration of squamous carcinoma cell Lines (SCC), Examinations of growth-aff ected cell populations show that SCC lines ME-180 and SiHa treated with IFN -beta undergo a specific slower progression through the S phase that seems to trigger cellular death. In combination treatment RA potentiates IFN-beta effect in SCC ME-180 but not in SiHa cell line, partially resistant to RA antiproliferative action. RA added as single agent affects cell proliferati on differently by inducing a slight GI accumulation. The IFN-beta-induced S phase lengthening parallels the increased expression of PML, a nuclear pho sphoprotein specifically up-regulated at transcriptional level by IFN, whos e overexpression induces cell growth inhibition and tumor suppression. We r eport that PML up-regulation may account for the alteration of cell cycle p rogression induced by IFN-beta in SCC by infecting cells with PML-PINCO rec ombinant retrovirus carrying the PML3 cDNA under the control of the 5' LTR. In fact PML overexpression reproduces the IFN-beta-induced S phase lengthe ning, These findings provide important insight into the mechanism of tumor suppressing function of PML and could allow PML to be included in the pathw ays responsible for IFN-induced cell growth suppression.