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Aberration of poly(adenosine diphosphate-ribose) metabolism in human colon adenomatous polyps and cancers
Abstract:
The activities of three principal enzymes engaged in the biosynthesis and degradation of poly(adenosine diphosphate-ribose) [poly(ADP-ribose)] were examined in cell nuclei isolated from adenomatous polyps (tubular adenomas of familial polyposis coli, villous adenoma, and tubulovillous adenoma), cancers, and normal mucosa of human colon. The activities of poly(ADP-ribose) synthetase in adenomatous polyps [161 +/- 46 (S.E.) pmol/min/mg DNA] and cancers (114 +/- 32 pmol/min/mg DNA) were, on an average, about 3 and 2 times, respectively, higher than those in normal mucosa (52 +/- 24 pmol/min/mg DNA); the difference was statistically significant (p less than 0.001). The activity of poly(ADP-ribose) glycohydrolase was also significantly high in adenomatous polyps (13.0 +/- 3.4 nmol/min/mg DNA), but not in cancers (10.1 +/- 2.5 nmol/min/mg DNA), compared with normal mucosa (5.2 +/- 1.4 nmol/min/mg DNA) (p less than 0.001). The activity of ADP-ribosyl protein lyase, in contrast, was lower in adenomatous polyps (152 +/- 40 pmol/min/mg DNA) than in normal mucosa (345 +/- 111 pmol/min/mg DNA) and cancers (288 +/- 80 pmol/min/mg DNA) (p less than 0.001). Analyses of reaction products with snake venom phosphodiesterase digestion revealed that poly(ADP-ribose) synthesized in nuclei of normal mucosa, adenomatous polyps, and cancers had the average chain lengths of 2.9, 1.7, and 9.7 ADP-ribose units, respectively. Based upon these values and total amounts of ADP-ribose incorporated, the amount of poly(ADP-ribose) synthesized per mg DNA in 30 min was calculated as 308, 1510, and 106 pmol in the above three types of colon tissues, respectively. These results suggested that a larger amount of monomers and short oligomers of ADP-ribose was synthesized in adenomatous polyps, while a smaller number of longer polymers was produced in cancers as compared with normal mucosa. Immunohistochemical analysis of these tissues using anti-poly(ADP-ribose) antibody supported this view.
Insights
Enzymes involved in poly(adenosine diphosphate-ribose) [poly(ADP-ribose)] metabolism show altered activity in colon adenomas and cancers. Poly(ADP-ribose) synthetase and glycohydrolase activities are elevated in polyps, while ADP-ribosyl protein lyase is decreased.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Poly(adenosine diphosphate-ribose) [poly(ADP-ribose)] is a crucial post-translational modification involved in DNA repair and gene regulation.
- Dysregulation of poly(ADP-ribose) metabolism has been implicated in various diseases, including cancer.
Purpose of the Study:
- To investigate the activities of key enzymes in poly(ADP-ribose) biosynthesis and degradation in human colon tissues.
- To compare enzyme activities and poly(ADP-ribose) chain lengths in normal mucosa, adenomatous polyps, and colon cancers.
Main Methods:
- Isolation of cell nuclei from human colon tissues (normal mucosa, adenomatous polyps, cancers).
- Assay of poly(ADP-ribose) synthetase, poly(ADP-ribose) glycohydrolase, and ADP-ribosyl protein lyase activities.
- Analysis of poly(ADP-ribose) chain lengths using snake venom phosphodiesterase digestion and immunohistochemistry.
Main Results:
- Poly(ADP-ribose) synthetase activity was significantly higher in adenomatous polyps and cancers compared to normal mucosa.
- Poly(ADP-ribose) glycohydrolase activity was elevated in adenomatous polyps but not in cancers.
- ADP-ribosyl protein lyase activity was lower in adenomatous polyps and cancers.
- Poly(ADP-ribose) chain lengths differed, with shorter chains in polyps and longer chains in cancers compared to normal mucosa.
Conclusions:
- Altered activities of poly(ADP-ribose) metabolizing enzymes are associated with colon adenomas and cancers.
- The study suggests distinct patterns of poly(ADP-ribose) synthesis in normal, adenomatous, and cancerous colon tissues.