RAPID NON-GENOMIC AND CONCENTRATION-DEPENDENT EFFECTS OF PROGESTERONE IN C4-I CELLS ON THE PROPOSED TUMOR-MARKER - RATIO BETWEEN EXTRACELLULAR CGMP AND CAMP LEVELS

Abstract

The extracellular cGMP levels or the ratio between extracellular levels of cGMP and cAMP (cGMP(ex)/cAMP(ex)) have been proposed as tumor marker for premalignant and malignant diseases of the uterine cervix. More than 50% of cervical cancers occur in premenopausal women and detailed information about hormonal and drug effects on the extracellular levels of cyclic nucleotides is of importance. In the present study we have investigated the effect of progesterone (0.1-100 mu M), theophylline (1-1000 mu M), probenecid (0.1-100 mu M) and verapamil (0.1-100 mu M) on cGMP(ex)/cAMP(ex) of C4-I cells (a human cell line derived from a squamous carcinoma of the uterine cervix). Within 30 min progesterone caused a concentration-dependent elevation of cGMP(ex)/cAMP(ex), whereas the other compounds had no marked effect. Identical results were obtained for C4-I cells in monolayer and in suspension. The effects were explained by the observation that progesterone stimulated cGMP efflux, but inhibited the cAMP efflux. The other compounds inhibited the export of both nucleotides to a similar degree. The present data suggest that progesterone affects the export of cyclic nucleotides in non-genomic manner and may hamper the interpretation of cGMP(ex)/cAMP(ex) in the luteal phase in premenopausal women with cancer of the uterine cervix.