The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells.

Abstract

The copper(II) complex A0 induces a type of non-apoptotic cell death also known as paraptosis. Paraptosis involves extensive endoplasmic reticulum vacuolization in the absence of caspase activation. A wide panel of human cancer cell lines was used to demonstrate differences in cytotoxicity by the paraptosis-inducing drug A0 and the metal-based pro-apoptotic drug cisplatin. Gene expression profiling of the human fibrosarcoma HT1080 cells showed that, while cisplatin induced p53 targets, A0 up-regulated genes involved in the unfolded protein response (UPR) and response to heavy metals. The cytotoxic effects of A0 were associated with inhibition of the ubiquitin-proteasome system and accumulation of ubiquitinylated proteins, in a manner dependent on protein synthesis. Cycloheximide inhibited the accumulation of ubiquitinylated proteins and hampered A0-induced cell death process. The occurrence of the UPR during A0-induced death process was shown by the increased abundance of spliced XBP1 mRNA, transient eIF2alpha phosphorylation, and a series of downstream events, including attenuation of global protein synthesis and increased expression of ATF4, CHOP, BIP, and GADD34. Mouse embryonic fibroblasts expressing a mutant eIF2alpha, which could not be phosphorylated, were more resistant to A0 than wild type cells, pointing to a pro-death role of eIF2alpha phosphorylation. A0 may thus represent the prototypical member of a new class of compounds that cause paraptotic cell death via mechanisms involving eIF2alpha phosphorylation and the UPR.

• Authors: Saverio Tardito, Claudio Isella, Enzo Medico, Luciano Marchiò, Elena Bevilacqua, Maria Hatzoglou, Ovidio Bussolati, Renata Franchi-Gazzola
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 36 Pg. 24306-19 (Sep 04 2009) ISSN: 0021-9258 [Print] United States
• PMID: 19561079 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Neoplasm Proteins
• Organometallic Compounds
• RNA, Messenger
• Ubiquitin
• Copper
• Proteasome Endopeptidase Complex
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Caco-2 Cells
• Cisplatin (pharmacology)
• Copper (pharmacology, therapeutic use)
• Drug Screening Assays, Antitumor
• Endoplasmic Reticulum (genetics, metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• HeLa Cells
• Humans
• Mice
• Neoplasm Proteins (biosynthesis, genetics)
• Neoplasms (drug therapy, genetics, metabolism)
• Organometallic Compounds (pharmacology, therapeutic use)
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Protein Folding (drug effects)
• RNA, Messenger (genetics, metabolism)
• Stress, Physiological (drug effects)
• Ubiquitin (genetics, metabolism)
• Ubiquitination (drug effects)