Colorectal cancer metastases affect the biochemical characteristics of the human liver β-adrenoceptor-G-protein-adenylate cyclase system

Abstract

The sympathetic-catecholamine system is involved in the regulation of hepatic metabolic pathways mainly through cAMP-linked β 2-adrenoceptors (β 2-ARs) in humans and to a lesser extent through cAMP-independent mechanisms, but no information is available about the possible biochemical changes of β 2-ARs and their signalling pathways in human colorectal cancer (CRC) and colorectal cancer hepatic metastases (CRCHM). Changes in density and distribution of β-ARs as well as in post-receptor signalling components were studied in membranes of human liver with CRCHM, and for comparison, in membranes of nonadjacent, non-metastatic human liver (NA-NM) obtained from 13 patients, using binding and competition binding studies. Studies were also carried out using normal and cancerous human colon tissues. In CRCHM, the density of β-ARs ( B max) was significantly reduced, compared to NA-NM liver tissues (40.09 ± 2.83 vs. 23.09 ± 3.24 fmol/mg protein; P < 0.001). A similar decrease in the β-AR density was observed in the colon with primary colorectal cancer compared to healthy colon (37.6 ± 2.2 vs. 23.8 ± 3.5 fmol/mg protein), whereas the affinity of ICYP binding to the receptor remained unaffected. Desensitized β-ARs were uncoupled from stimulatory G-protein (G S), as total density of β-adrenoceptors in the high affinity state was significantly reduced. Concomitantly, CRCHM elicited decrease in the catalytic adenylate cyclase (AC) activity (cAMP formation) in response to isoproterenol plus GTP or forskolin or NaF. In NA-NM and CRCHM liver, the inhibition–concentration curves of ICI 118.551 showed the presence of a homogeneous population of the β 2-AR subtypes. Neither the binding patterns nor the inhibition constant ( K i) of ICI 118.551 were altered in CRCHM. In CRCHM, the hepatic β-AR-G-protein(s)-AC signalling system was markedly impaired, thus, these changes may well influence β-AR-mediated functions in both organs.