Proteome analysis of rat hepatomas: carcinogen-dependent tumor-associated protein variants.
Proteome analysis led to the identification and characterization of tumor-associated protein variants by two-dimensional electrophoresis and mass spectrometry. We focused on comparing the influence of genotoxic nitroso compounds N-methyl-N-nitrosourea, diethylnitrosamine and N-nitrosomorpholine and the nongenotoxic peroxisome proliferator Nafenopin as tumor-inducing agents on the protein pattern of rat hepatomas. We found several tumor-associated variants that represent members of the aldo-keto reductase superfamily. Their induction and/or inhibition was specifically related to the carcinogen used for tumor induction. The most prominent tumor-associated protein, rat aldose reductase-like protein-1 (rARLP-1) (69% sequence identity to lens aldose reductase) and three additional types of rARLP-1 were detected in nitroso compound-induced rat hepatomas, while rat aldo-keto reductase protein-c (Rak-c), a novel tumor-associated variant (65% sequence identity with 3alpha-hydroxysteroid dehydrogenase) was discovered in N-methyl-N-nitrosourea-induced hepatomas only. 3Alpha-hydroxysteroid dehydrogenase and delta4-3-ketosteroid-5beta-reductase, both liver-specific enzymes, were reduced in amount in all hepatomas investigated, independent of their mode of induction. We conclude, that detoxification enzymes like 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) and delta4-3-ketosteroid-5beta-reductase (5beta-Red) might be replaced in hepatomas by tumor-associated proteins that are often present in the embryonal state, like the rARLPs or the Rak-c protein. Their induction appears to reflect an altered constitutive pattern of detoxification enzymes, detoxifying toxic aldehydes being induced by nitroso compounds. In contrast, members of the aldo-keto reductase superfamily have not been found in Nafenopin-induced hepatomas. The pattern of tumor-associated protein variants is apparently characteristic for a given group of initiating carcinogens. The hypothesis is proposed that carcinogens leave specific fingerprints at the proteome level of manifest liver tumors.
Zeindl-Eberhart
E
E
Institute of Pathology, University of Munich, Germany.
Klugbauer
S
S
Dimitrijevic
N
N
Jungblut
P R
PR
Lamer
S
S
Rabes
H M
HM
D000449:Aldehyde Reductase / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D000074408:Aldo-Keto Reductases; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000494:pharmacology / Q000633:toxicity; D015180:Electrophoresis, Gel, Two-Dimensional; D005326:Fetal Proteins / Q000032:analysis / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D008658:Inactivation, Metabolic / Q000235:genetics*; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology / Q000633:toxicity; D008969:Molecular Sequence Data; D009255:Nafenopin / Q000494:pharmacology / Q000633:toxicity; D009363:Neoplasm Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D009602:Nitrosamines / Q000494:pharmacology / Q000633:toxicity; D009928:Organ Specificity; D020025:Peroxisome Proliferators / Q000494:pharmacology / Q000633:toxicity; D020543:Proteome; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013382:Subtraction Technique
D002273:Carcinogens; D005326:Fetal Proteins; D007527:Isoenzymes; D009363:Neoplasm Proteins; D009602:Nitrosamines; D020025:Peroxisome Proliferators; D020543:Proteome; D009255:Nafenopin; D004052:Diethylnitrosamine; C002741:N-nitrosomorpholine; D008770:Methylnitrosourea; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase