Serum thioredoxin reductase is highly increased in mice with hepatocellular carcinoma and its activity is restrained by several mechanisms

• Published in: Free radical biology & medicine 2016-10, Vol.99, p.426-435
• Main Authors: Zhang, Le, Cheng, Qing, Zhang, Longjie, Wang, Yijun, Merrill, Gary F., Ilani, Tal, Fass, Deborah, Arnér, Elias S.J., Zhang, Jinsong
• Format: Article
• Language: English
• Subjects: Alanine Transaminase - genetics; Alanine Transaminase - metabolism; Aldehydes - metabolism; Aldehydes - pharmacology; Animals; Antineoplastic Agents - pharmacology; Auranofin - pharmacology; Biomarker; Carboplatin - pharmacology; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cisplatin - pharmacology; Hepatocellular carcinoma; Liver Neoplasms - drug therapy; Liver Neoplasms - enzymology; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred Strains; Neoplasm Transplantation; Oxidoreductases Acting on Sulfur Group Donors - blood; Oxidoreductases Acting on Sulfur Group Donors - genetics; Protoporphyrins - metabolism; Protoporphyrins - pharmacology; QSOX1; Serum; Thioredoxin reductase; Thioredoxin-Disulfide Reductase - antagonists & inhibitors; Thioredoxin-Disulfide Reductase - blood; Thioredoxin-Disulfide Reductase - genetics
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2016.08.028

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. [Display omitted] •Serum TrxR activity is increased in mice carrying hepatocellular carcinoma tumors.•Serum ALT levels do not parallel those of TrxR.•Serum TrxR activity is restrained by several different mechanisms shown as follows.•Counteracted by serum oxidase that is identified as QSOX1.•Inhibited by certain chemotherapeutic agents and endogenous electrophilic agents.