Thioredoxin-mimetic peptides (TXM) reverse auranofin induced apoptosis and restore insulin secretion in insulinoma cells

Moshe Cohen-Kutner, Lena Khomsky, Michael Trus, Yonatan Aisner, Masha Y. Niv, Moran Benhar, Daphne Atlas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The thioredoxin reductase/thioredoxin system (TrxR/Trx1) plays a major role in protecting cells from oxidative stress. Disruption of the TrxR-Trx1 system keeps Trx1 in the oxidized state leading to cell death through activation of the ASK1-Trx1 apoptotic pathway. The potential mechanism and ability of tri- and tetra-oligopeptides derived from the canonical -CxxC- motif of the Trx1-active site to mimic and enhance Trx1 cellular activity was examined. The Trx mimetics peptides (TXM) protected insulinoma INS 832/13 cells from oxidative stress induced by selectively inhibiting TrxR with auranofin (AuF). TXM reversed the AuF-effects preventing apoptosis, and increasing cell-viability. The TXM peptides were effective in inhibiting AuF-induced MAPK, JNK and p38 MAPK phosphorylation, in correlation with preventing caspase-3 cleavage and thereby PARP-1 dissociation. The ability to form a disulfide-bridge-like conformation was estimated from molecular dynamics simulations. The TXM peptides restored insulin secretion and displayed Trx1 denitrosylase activity. Their potency was 10-100-fold higher than redox reagents like NAC, AD4, or ascorbic acid. Unable to reverse ERK1/2 phosphorylation, TXM-CB3 (NAc-Cys-Pro-Cys amide) appeared to function in part, through inhibiting ASK1-Trx dissociation. These highly effective anti-apoptotic effects of Trx1 mimetic peptides exhibited in INS 832/13 cells could become valuable in treating adverse oxidative-stress related disorders such as diabetes.

Original languageAmerican English
Pages (from-to)977-990
Number of pages14
JournalBiochemical Pharmacology
Volume85
Issue number7
DOIs
StatePublished - 1 Apr 2013

Bibliographical note

Funding Information:
This study was funded by the Betty Feffer Fund , the H.L. Lauterbach Fund and NOFAR grant of the Israeli Ministry of Industry for D.A. The Haya and Shlomo Margalit Fund for M.C.-K., Niedersachsen-Israeli Research Foundation and U.S.-Israel Binational Science Foundation Grant no. 2007296 to M.Y.N.

Keywords

  • ASK1
  • Apoptosis
  • Diabetes
  • Insulin secretion
  • MAPK
  • Molecular dynamics
  • Oxidative stress
  • Thioredoxin

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