Cyclic adenosine 3',5'-monophosphate binding proteins in human colorectal cancer and mucosa

Abstract

Summary Cyclic AMP Binding Proteins (cAMP-BP) levels have been measured by means of a competitive binding assay in the cytosols of 50 human colorectal cancers. These levels have been related to those in mucosa both adjacent to and distant from the tumour in the same patients. Cyclic AMP-BP were higher in tumour than in either adjacent (P<0.000001) or distant mucosa (P<0.00001). Binding of cAMP in adjacent mucosa was lower than that in distant mucosa (P<0.0001). There was no significant difference in the level of binding between tumours arising from different sites in the colon and binding was not related to age or sex of the patient. However, binding was higher in Dukes' B than Dukes' C cancers (P<0.005). There was also a trend for cAMP binding levels to be higher in moderately differentiated than in poorly differentiated cancers (P = 0.07). Thus cAMP-BP appear to be over-expressed in human colorectal cancers and levels are related to the stage and grade.Cyclic adenosine 3',5'-monophosphate (cAMP) functions as a secondary messenger for a wide range of hormones releasing factors and drugs. The cAMP signalling system also interacts with other signalling pathways that are used by locally-acting growth factors (Olashaw & Pledger, 1988) to bring about co-ordinated control of basic cell processes such as proliferation and differentiation. Cyclic AMP exerts all its known effects through binding to and activating a specific cAMPdependent protein kinase, also known as Protein Kinase A (PK-A) (Taylor et al., 1989). PK-A is a tetrameric holoenzyme comprising two regulatory units (R), and two catalytic units (C). R units, also known as cAMP binding proteins (cAMP-BP) act as pseudosubstrate for the C units and so prevent them from carrying out phosphorylation within the cell (Shenolikar, 1988). Activation of PK-A follows binding of cAMP to R units and their dissociation from the C unit. As well as leading to protein phosphorylation, activation PK-A also brings about changes in expression of cAMP dependent genes, although the exact mechanisms are, as yet, unclear (Roesler et al., 1988). Conventionally, cAMP has been considered a negative signal to cellular proliferation although stimulatory effects have been described depending on the cell type, phase in the cell cycle and presence of other growth factors (Dumont et al., 1989). Cyclic AMP analogues have been shown to inhibit the growth and promote the differentiation of a number of human cancer cell lines in vitro including those derived from colorectal cancer (Ally et al., 1988). In animal studies the production of colonic tumours by chemical carcinogens has been associated with decreased levels of PK-A activity (DeRubertis & Craven, 1980). Furthermore, cAMP and cAMP-dependent protein kinase levels have been reported to be lower in human colorectal cancers and villous adenomas than in normal mucosa (Alexandrov et al., 1986). By contrast, in breast cancer cAMP-BP levels are of independent prognostic significance (Miller et al., 1990) with higher levels of binding being associ...

Cyclic adenosine 3',5'-monophosphate-binding proteins in human ovarian cancers

“…Certain tumours also possessed binding proteins with molecular weight of either 43 or 39 kDa. The 48 and 52 kDa species probably correspond to the regulatory subunits of protein kinase A (RI and RII respectively), which have been characterised in different tissues (Eppenberger et al, 1980;Tortora et al, 1989;Bradbury et al, 1991;Miller et al, 1993). The 37 kDa protein has been suggested to be a product resulting from proteolytic degradation of the regulatory subunits, and the relatively high levels of this protein are consistent with our suspicion that ovarian tumour cytosols are more.…”

“…The results showed that high cAMP-binding protein levels are an indicator of poor prognosis. In contrast, in colorectal tumours low levels of binding appear to be associated with markers of poor prognosis such as advanced Dukes stage and poor histological grade (Bradbury et al, 1991). As a prelude to an evaluation of the clinical utility of cAMP-binding measurements in ovarian cancer, the present paper describes the characterisation of an assay that may be used routinely to assess levels of binding protein in this tumour type.…”

Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa

“…This is the first study to have characterised the pattern of PK-A R-subunit expression in human colorectal tissues, although our previous work has shown that the periphery of human colorectal cancers may possess increased total cAMPbinding levels (Bradbury et al, 1991). main types with molecular weights of 48, 50 and 52 kDa.…”

“…Previous work has shown that human colorectal cancers bind significantly more cAMP than related benign mucosa, suggesting that the development of colorectal cancer is associated with an abnormality in cAMP-BP expression (Bradbury et al, 1991). Furthermore, cAMP analogues inhibit the growth and promote the differentiation of a human colorectal cancer cell line together with a reduction in RI and an increase in RII expression (Tagliaferri et al, 1988).…”

Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIα subunit of protein kinase A after oral administration

“…Increased expression of the RI␣ subunit of PKA correlates with cell proliferation and neoplastic growth (2). Overexpression of the RI␣ subunit of PKA occurs in various human tumor tissues and cell lines including cancers of breast (3)(4)(5), ovary (6,7), lung (8), and colon (9)(10)(11). Furthermore, overexpression of the RI␣ subunit of PKA correlates with malignancy and poor prognosis in cancer patients (5)(6)(7).…”