TCDD suppression of tissue transglutaminase stimulation by retinoids in malignant human keratinocytes

The human keratinocyte line SCC-4 is a model system in which to explore the mechanism by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) interferes w ith the action of hormones in the steroid receptor superfamily. In present work, retinoid induction of tissue transglutaminase mRNA was suppressed 60- 70% by 10 nM TCDD in the human squamous carcinoma cell line SCC-4. This eff ect occurred without enhanced degradation of the mRNA and thus appeared to result from altered transcription. The actions of all-trans-retinoic acid a nd the synthetic retinoid TTNPB ((E)4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetram ethyl-2-naphthylenyl)-1-propenyl] benzoic acid), which resists metabolic de gradation, were suppressed to the same extent without obvious changes in th eir EC(50)s. In addition, TCDD suppression of reporter transcription, drive n by a retinoic acid response element, was not evident in transient or stab le transfections of SCC-4 cells. Sodium butyrate (3 mM) alone induced tissu e transglutaminase and augmented retinoid induction. In the presence of but yrate, TCDD acted as an inducer and did not reduce retinoid stimulation. Re tinoic acid induction of tissue transglutaminase displayed a lag phase of > 24 h, indicating that the induction has an indirect component. Rather than depleting active retinoid in the culture medium or generally inactivating r etinoid receptor function, TCDD may suppress retinoid action in this case b y interfering with the late phase of induction.