GROWTH FACTOR-MEDIATED MECHANISMS OF NICOTINE-DEPENDENT CARCINOGENESIS

The direct effect of nicotine on the expression of receptors for the t umor necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta) and the internalization, intracellular distribution an d stability of these growth factors in cervical cancer cell line SiHa was studied. Nicotine at concentrations in the range 0.05-0.25% inhibi ted cell growth and it exerted strong apoptotic and cytolytic effects at concentrations above 0.5%. Nicotine at 0.1% stabilized and protecte d from degradation [I-125]TNF alpha and [I-125]TGF beta internalized b y cervical cancer SiHa cell line. In the absence of nicotine, [I-125]T NF alpha and [I-125]TGF beta were internalized during the first hour o f incubation and localized mainly in the cytoplasm and in smaller amou nts in the nucleus. After 1 day of cell exposure to growth factors, on ly traces of radioactivity were detected inside the cells, which indic ated that both growth factors were rapidly degraded. In the presence o f nicotine, both [I-125]TNF alpha and [I-125]TGF beta were detected in high quantities and in a non-degraded form in the cytoplasm and chrom atin during 5 days of incubation. In addition to the lack of growth fa ctor degradation, the presence of nicotine induced a nuclear accumulat ion of growth factors, with up to 37% of the internalized [I-125]TGF b eta being in the chromatin. An increased intracellular accumulation of [I-125]TNF alpha and [I-125]TGF beta in cells exposed to nicotine occ urred without changes in expression of the cell surface receptors. Nuc lear accumulation of TGF beta was followed by increased RNA synthesis and a switch from the growth-promoting action of TGF beta to the stron g growth inhibitory effect. Inhibition of the lysosomal degradation of growth factors by nicotine is discussed as a potential mechanism of t obacco-induced carcinogenesis.