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The Thioxotriazole Copper(II) Complex A0 Induces Endoplasmic Reticulum Stress and Paraptotic Death in Human Cancer Cells
- Source :
- Journal of Biological Chemistry. 284:24306-24319
- Publication Year :
- 2009
- Publisher :
- Elsevier BV, 2009.
-
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.
- Subjects :
- Proteasome Endopeptidase Complex
Protein Folding
Programmed cell death
XBP1
Physiological
Messenger
Antineoplastic Agents
Apoptosis
Cycloheximide
Biology
Drug Screening Assays
Stress
Endoplasmic Reticulum
Biochemistry
Paraptosis
Mice
chemistry.chemical_compound
Molecular Basis of Cell and Developmental Biology
Stress, Physiological
Neoplasms
Organometallic Compounds
Animals
Humans
RNA, Messenger
Molecular Biology
Neoplastic
Ubiquitin
Gene Expression Profiling
Endoplasmic reticulum
Caco-2 Cells
Cisplatin
Copper
Antitumor
Gene Expression Regulation
Hela Cells
Neoplasm Proteins
RNA
Ubiquitination
Cell Biology
Molecular biology
Cell biology
Gene Expression Regulation, Neoplastic
chemistry
Cell Death Process
Unfolded protein response
Drug Screening Assays, Antitumor
HeLa Cells
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 284
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....337d933fa2dcaef710cf541b5cbf2935