Alterations of signal transduction pathways involved in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced malignant transformation of human cells in culture

Effects of signal transduction pathways in TCDD-induced neoplastic transformation of human cells were assessed with respect to PLC-coupled signaling pathways, adenylyl cyclase-mediated responses and PKC isozyme expressions. A lower stimulation of the intracellular free calcium levels with exposure to extracellular ATP or histamine was observed in the transformed cells, as compared to the parental cells. While the steady-state level of IP3 was higher in the transformed cells, the magnitude of stimulation of IP3 generation by ATP or histamine was significantly lower in the transformed cells than the parental cells. These results indicate that a downregulation of PLC-coupled signaling pathways may be involved in the TCDD-induced transformation of human cells. While the steady-state levels of cAMP accumulation were similar between the two cell lines, treatment of PGE2, a potent differentiation inducer, stimulated a higher accumulation of CAMP in the parental cells but isoproterenol, a typical β-adrenergic agonist, did not induce a significant difference between the two cell lines. These results suggest that desensitization of cAMP-mediated responses to extracellular signals including differentiation signals may be associated with a possible mechanism of the carcinogenesis. Elevated expression of PKC-α, -γ, -ζ, , -λ, and -ι were observed ion TCDD-transformed cells, indicating a possible association of altered expression of PKC isozymes with TCDD-induced transformation of human cells. The present study demonstrates that alterations of signal transduction pathways are involved in the TCDD-induced transformation of human cells and provides, a valuable basis to investigate effects of signaling pathway as a possible mechanism of TCDD-induced carcinogenesis in human cells.