Induction of caspase 8 by interferon γ renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB Journal Article
| Authors: | Yang, X.; Merchant, M. S.; Romero, M. E.; Tsokos, M.; Wexler, L. H.; Kontny, U.; Mackall, C. L.; Thiele, C. J. |
| Article Title: | Induction of caspase 8 by interferon γ renders some neuroblastoma (NB) cells sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but reveals that a lack of membrane TR1/TR2 also contributes to TRAIL resistance in NB |
| Abstract: | The resistance of neuroblastoma (NB) cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis has been attributed to a lack of caspase 8 expression. Here we demonstrate a clinically applicable molecular targeting strategy that not only increases caspase 8 expression ex vivo in NB cell lines but also in the tumor tissues of NB patients receiving IFN-γ treatment. We identify the functional caspase 8 promoter, which is different from the methylated region reported previously, and show promoter activity is up-regulated by IFN-γ through a IFN-γ activation site-containing region. IFN-γ also induces TRAIL expression in NB cell lines. However, the IFN-γ restoration of caspase 8 in some NB cells revealed persistent TRAIL resistance in most NB cell lines examined. This additional lesion in the TRAIL path is because of a loss of cell membrane TRAIL receptors (TR1/TR2) not only in cell lines but in most of the NB tumor tissues evaluated. Restoration of TR2 expression by transfection enhances IFN-γ-induced TRAIL sensitivity. Furthermore, we have found that we can improve TRAIL sensitivity in NB by reconstituting caspase 8 with IFN-γ and TR2 with chemotherapeutic agents. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; promoter region; drug activity; antineoplastic agents; drug targeting; apoptosis; apoptosis regulatory proteins; transcription, genetic; cancer cell culture; drug resistance, neoplasm; tumor cells, cultured; caspases; transfection; dna methylation; genetic transfection; tumor necrosis factor-alpha; gamma interferon; recombinant gamma interferon; neuroblastoma; rna, messenger; membrane glycoproteins; tumor necrosis factor related apoptosis inducing ligand; caspase 8; caspase 9; drug sensitivity; enzyme induction; gene activity; receptors, tumor necrosis factor; tnf-related apoptosis-inducing ligand; receptors, tnf-related apoptosis-inducing ligand; interferon type ii; membrane receptor; humans; human; priority journal; article; protein tr1; protein tr2 |
| Journal Title: | Cancer Research |
| Volume: | 63 |
| Issue: | 5 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2003-03-01 |
| Start Page: | 1122 |
| End Page: | 1129 |
| Language: | English |
| PUBMED: | 12615731 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 12 September 2014 -- Source: Scopus |
