title: Serum thioredoxin reductase is highly increased in mice with hepatocellular carcinoma and its activity is restrained by several mechanisms.
abstract: Increased thioredoxin reductase (TrxR) levels in serum were recently identified as possible prognostic markers for human prostate cancer or hepatocellular carcinoma. We had earlier shown that serum levels of TrxR protein are very low in healthy mice, but can in close correlation to alanine aminotransferase (ALT) increase more than 200-fold upon chemically induced liver damage. We also found that enzymatic TrxR activity in serum is counteracted by a yet unidentified oxidase activity in serum. In the present study we found that mice carrying H22 hepatocellular carcinoma tumors present highly increased levels of TrxR in serum, similarly to that reported in human patients. In this case ALT levels did not parallel those of TrxR. We also discovered here that the TrxR-antagonistic oxidase activity in serum is due to the presence of quiescin Q6 sulfhydryl oxidase 1 (QSOX1). We furthermore found that the chemotherapeutic agents cisplatin or auranofin, when given systemically to H22 tumor bearing mice, can further inhibit TrxR activities in serum. The TrxR serum activity was also inhibited by endogenous electrophilic inhibitors, found to increase in tumor-bearing mice and to include protoporphyrin IX (PpIX) and 4-hydroxynonenal (HNE). Thus, hepatocellular carcinoma triggers high levels of serum TrxR that are not paralleled by ALT, and TrxR enzyme activity in serum is counteracted by several different mechanisms. The physiological role of TrxR in serum, if any, as well as its potential value as a prognostic marker for tumor progression, needs to be studied further.
authors: State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China.
authors: Le
authors: L
authors: Zhang
authors: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors: Qing
authors: Q
authors: Cheng
authors: State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China.
authors: Longjie
authors: L
authors: Zhang
authors: State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China.
authors: Yijun
authors: Y
authors: Wang
authors: Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA.
authors: Gary F
authors: GF
authors: Merrill
authors: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors: Tal
authors: T
authors: Ilani
authors: Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors: Deborah
authors: D
authors: Fass
authors: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors: Elias S J
authors: ESJ
authors: Arnér
authors: State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China. Electronic address: zjs@ahau.edu.cn.
authors: Jinsong
authors: J
authors: Zhang
mesh_terms: D000410:Alanine Transaminase / Q000235:genetics / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001310:Auranofin / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000097:blood / Q000235:genetics*; D011524:Protoporphyrins / Q000378:metabolism / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics*
chemical_list: D000447:Aldehydes; D000970:Antineoplastic Agents; D011524:Protoporphyrins; D001310:Auranofin; D016190:Carboplatin; C028025:protoporphyrin IX; D050862:Oxidoreductases Acting on Sulfur Group Donors; D013880:Thioredoxin-Disulfide Reductase; C000625753:QSOX1 protein, mouse; D000410:Alanine Transaminase; C027576:4-hydroxy-2-nonenal; D002945:Cisplatin
keywords: Biomarker; Hepatocellular carcinoma; QSOX1; Serum; Thioredoxin reductase