Retinoic Acid and IFN Inhibition of Cell Proliferation is Associated with Apoptosis in Squamous Carcinoma Cell Lines: Role of IRF-1 and TGase II-dependent Pathways

Both retinoids and IFNs are known to inhibit proliferation of many normal and transformed cells and to have an in vivo antitumor effect against a variety of cancers, including squamous cell carcinoma. Because the combination of IFNs and all-trans retinoic acid (RA) could improve their antitumor effectiveness (depending on the histological origin and state of differentiation of the cells), we compared the activity of RA and/or IFN-alpha 2b with regard to the mechanism of growth inhibition of ME180 and SiHa cell lines, derived from squamous cervix carcinoma at different stages of differentiation. We reported previously that, in the ME180 cell line, the combined treatment significantly increased the growth inhibitory effect of the single agents. Here, we show that the SiHa cell line appears more sensitive to IFN-alpha 2b than the ME180 cell line, and resistant to RA, which does not significantly inhibit SiHa cell growth. Induction of apoptotic cell death clearly occurs and correlates with the inhibition of cell proliferation in both cell lines. It is interesting that the induction of the transcription factor IFN regulatory factor 1 correlates with the subsequent induction of apoptosis, whereas TGase I and II expression does not. In particular, TGase I and II appear differentially expressed in the ME180 and SiHa cell lines; i.e., TGase I is expressed in ME180 and specifically inhibited by RA, whereas TGase II is expressed in SiHa. It is interesting that both IFN-alpha and RA are able to increase TGase II expression and activity in this cell line.