Colorectal cancer metastases affect the biochemical characteristics of the human liver beta-adrenoceptor-G-protein-adenylate cyclase system.
The sympathetic-catecholamine system is involved in the regulation of hepatic metabolic pathways mainly through cAMP-linked beta2-adrenoceptors (beta2-ARs) in humans and to a lesser extent through cAMP-independent mechanisms, but no information is available about the possible biochemical changes of beta2-ARs and their signalling pathways in human colorectal cancer (CRC) and colorectal cancer hepatic metastases (CRCHM). Changes in density and distribution of beta-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 beta-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 beta-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 beta-ARs were uncoupled from stimulatory G-protein (G(S)), as total density of beta-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 beta2-AR subtypes. Neither the binding patterns nor the inhibition constant (K(i)) of ICI 118.551 were altered in CRCHM. In CRCHM, the hepatic beta-AR-G-protein(s)-AC signalling system was markedly impaired, thus, these changes may well influence beta-AR-mediated functions in both organs.
Kassahun
Woubet T
WT
Department of Surgery II, Faculty of Medicine, University of Leipzig, Liebig Strasse 20a, 04103 Leipzig, Germany.
Ungemach
Fritz R
FR
Gottschalk
Jutta
J
Hauss
Johann
J
Abraham
Getu
G
D000262:Adenylyl Cyclases / Q000502:physiology*; D000368:Aged; D002462:Cell Membrane / Q000502:physiology; D015179:Colorectal Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D020120:Iodocyanopindolol / Q000378:metabolism; D007545:Isoproterenol / Q000378:metabolism; D008099:Liver / Q000502:physiology; D008113:Liver Neoplasms / Q000503:physiopathology* / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D020120:Iodocyanopindolol; D000262:Adenylyl Cyclases; D007545:Isoproterenol