ABSTRACT
Carcinoma of the uterine cervix represents the second most frequent female malignancy worldwide, but few biochemical tumour markers have been implemented into clinical practice. Elevated extracellular guanosine 3', 5'-cyclic monophosphate (cGMP) levels have been reported to be a sensitive, early and reliable marker for screening relapse in carcinoma of the uterine cervix. The mechanism behind this observation remains unknown. The possibility exists that the cancer cells develop resistance to the antiproliferative effect of high intracellular cGMP levels. The enhanced cGMP expression may originate from either an increase in cellular export capacity by increased expression of member 5 in subfamily C of ATP-Binding-Cassette transporters (ABCC5), or increased substrate (cGMP) levels for this pump. The latter situation occurs with increased expression of inducible nitric oxide synthase (iNOS) and/or soluble guanylyl cyclase (sGC) and/or reduced expression of member 5 of the cyclic nucleotide phosphodiesterases (PDE5). Four transformed human cell lines derived from carcinomas of the uterine cervix (C-4 I, C-33 A, SiHa and ME-180 cells) and one non-transformed human cell line (WI-38) were included in the study in order to unveil which biokinetic components are involved. The expressions of iNOS, sGC, PDE5 and ABCC5 in the initial and final phase of the exponential growth curve were compared. Assuming that the WI-38 control cells mimic the situation in a normal tissue, iNOS remains un-expressed during proliferation, and the expression of sGC is low but shows a clear increase during exponential growth. PDE5 is highly expressed and increases (≈130%) during growth whereas ABCC5 exhibited low to moderate expression, with a moderate increase (≈40%) during growth. The malignant cells exhibited moderate ABCC5 expression with a distinct increase during exponential growth, whereas PDE5 expression remained virtually unchanged. Dysregulation of the cGMP biokinetics in growing malignant cells may account for the elevation of extracellular cGMP observed in patients with carcinoma of the uterine cervix.
