Differential genomic and proteomic profiling of glioblastoma cells exposed to terpyridineplatinum(II) complexes.
Terpyridineplatinum(II) complexes (TPCs) efficiently inhibit the proliferation of glioblastoma cells in vitro and have been tested successfully in a rodent glioblastoma model. Apart from intercalation with DNA, the major mechanism of action of TPCs is a very potent and specific interaction with the human selenoprotein thioredoxin reductase (TrxR). TrxR plays a crucial role in cellular redox homeostasis and protection against oxidative damage. In many malignant cells the thioredoxin system is upregulated, promoting tumor growth and progression. Thus, the thioredoxin system has been proposed to be an attractive target for cancer therapy. This study gives the first comprehensive overview of the effects of TPCs on the transcriptome and proteome of glioblastoma cells. We reveal that under TPC treatment, mechanisms countersteering TrxR inhibition are activated in parallel to DNA-damage-responsive pathways. TPC pressure results in long-term compensatory upregulation of TrxR expression. In parallel, p53 is activated, leading to a range of regulations typical for cell-cycle-arrested cells such as upregulation of CDKN1A, induction of GADD45, inhibition of eIF5A maturation, and reduced phosphorylation of stathmin. We also show that TPCs induce endoplasmic reticulum stress, as they activate the unfolded protein response. This profiling study provides a thorough insight into the spectrum of cellular events resulting from specific TrxR inhibition and characterizes the TPC mode of action.
Interdisciplinary Research Center, Justus-Liebig University, Giessen, Germany.
Sasa
S
Koncarevic
Sabine
S
Urig
Klaus
K
Steiner
Stefan
S
Rahlfs
Christel
C
Herold-Mende
Holger
H
Sueltmann
Katja
K
Becker
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010448:Peptide Initiation Factors / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D020543:Proteome; D011725:Pyridines / Q000494:pharmacology*; D016601:RNA-Binding Proteins / Q000378:metabolism; D050777:Stathmin / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097574:Eukaryotic Translation Initiation Factor 5A; D000097642:GADD45 Proteins
D050759:Cyclin-Dependent Kinase Inhibitor p21; D007364:Intercalating Agents; D047908:Intracellular Signaling Peptides and Proteins; D010448:Peptide Initiation Factors; D010636:Phenols; D020543:Proteome; D011725:Pyridines; D016601:RNA-Binding Proteins; D050777:Stathmin; D013438:Sulfhydryl Compounds; D013880:Thioredoxin-Disulfide Reductase; D016159:Tumor Suppressor Protein p53; D000097574:Eukaryotic Translation Initiation Factor 5A; D000097642:GADD45 Proteins; C505584:4-mercaptophenol; C029347:2-thiopyridine