PMID- 27581528 OWN - NLM STAT- MEDLINE DCOM- 20180102 LR - 20180103 IS - 1873-4596 (Electronic) IS - 0891-5849 (Linking) VI - 99 DP - 2016 Oct TI - Serum thioredoxin reductase is highly increased in mice with hepatocellular carcinoma and its activity is restrained by several mechanisms. PG - 426-435 LID - S0891-5849(16)30409-9 [pii] LID - 10.1016/j.freeradbiomed.2016.08.028 [doi] AB - 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. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Zhang, Le AU - Zhang L AD - State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China. FAU - Cheng, Qing AU - Cheng Q AD - Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. FAU - Zhang, Longjie AU - Zhang L AD - State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China. FAU - Wang, Yijun AU - Wang Y AD - State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China. FAU - Merrill, Gary F AU - Merrill GF AD - Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA. FAU - Ilani, Tal AU - Ilani T AD - Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. FAU - Fass, Deborah AU - Fass D AD - Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. FAU - Arner, Elias S J AU - Arner ESJ AD - Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden. FAU - Zhang, Jinsong AU - Zhang J AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160828 PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Aldehydes) RN - 0 (Antineoplastic Agents) RN - 0 (Protoporphyrins) RN - 3H04W2810V (Auranofin) RN - BG3F62OND5 (Carboplatin) RN - C2K325S808 (protoporphyrin IX) RN - EC 1.8.- (Oxidoreductases Acting on Sulfur Group Donors) RN - EC 1.8.1.9 (Thioredoxin-Disulfide Reductase) RN - EC 1.8.3.2 (QSOX1 protein, mouse) RN - EC 2.6.1.2 (Alanine Transaminase) RN - K1CVM13F96 (4-hydroxy-2-nonenal) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Alanine Transaminase/genetics/metabolism MH - Aldehydes/metabolism/pharmacology MH - Animals MH - Antineoplastic Agents/pharmacology MH - Auranofin/pharmacology MH - Carboplatin/pharmacology MH - Carcinoma, Hepatocellular/drug therapy/*enzymology/genetics/pathology MH - Cell Line, Tumor MH - Cisplatin/pharmacology MH - Liver Neoplasms/drug therapy/*enzymology/genetics/pathology MH - Male MH - Mice MH - Mice, Inbred Strains MH - Neoplasm Transplantation MH - Oxidoreductases Acting on Sulfur Group Donors/blood/*genetics MH - Protoporphyrins/metabolism/pharmacology MH - Thioredoxin-Disulfide Reductase/antagonists & inhibitors/blood/*genetics OTO - NOTNLM OT - Biomarker OT - Hepatocellular carcinoma OT - QSOX1 OT - Serum OT - Thioredoxin reductase EDAT- 2016/10/23 06:00 MHDA- 2018/01/03 06:00 CRDT- 2016/09/02 06:00 PHST- 2016/06/24 00:00 [received] PHST- 2016/08/23 00:00 [revised] PHST- 2016/08/26 00:00 [accepted] PHST- 2016/10/23 06:00 [pubmed] PHST- 2018/01/03 06:00 [medline] PHST- 2016/09/02 06:00 [entrez] AID - S0891-5849(16)30409-9 [pii] AID - 10.1016/j.freeradbiomed.2016.08.028 [doi] PST - ppublish SO - Free Radic Biol Med. 2016 Oct;99:426-435. doi: 10.1016/j.freeradbiomed.2016.08.028. Epub 2016 Aug 28.