Selective TRAIL-triggered apoptosis due to overexpression of TRAIL death receptor 5 (DR5) in P-glycoprotein-bearing multidrug resistant CEM/VBL1000 human leukemia cells

Soo Jung Park, Khadijeh Bijangi-Vishehsaraei, Ahmad R. Safa

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

The death-inducing cytokine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), holds enormous promise as a cancer therapeutic due to its highly selective apoptosis-inducing action on neoplastic versus normal cells. Our results revealed that TRAIL selectively triggered apoptosis in the P-glycoprotein (P-gp, ABCB1) and DR5 overexpressing CEM/VBL1000 multidrug resistant leukemia cell line, but not in the parental CEM cells. Moreover, TRAIL treatment reduced P-gp expression in these cells. Mechanistic analysis of TRAIL-induced apoptosis revealed that TRAIL hypersensitivity is due to robust upregulation of the TRAIL receptor DR5 at the protein and mRNA levels during development of MDR in the CEM/VBL1000 variant. DR5 upregulation was independent of the level of expression of endoplasmic reticulum stress regulator C/EBP homologous transcription factor (CHOP/GADD153). TRAILtriggered apoptosis was associated with increased expression of FADD; activation of caspases-3, -8, -9, and -10; and cytochrome c release from mitochondria. Therefore, both the extrinsic and intrinsic apoptosis pathways are involved in this process. These findings for the first time reveal that TRAIL treatment selectively causes apoptosis in P-gpoverexpressing CEM/VBL1000 cells through strong upregulation of DR5. Moreover, this hypersensitivity to TRAIL and its effect on reducing P-gp expression in these cells hold significant clinical implications for using TRAIL to eradicate MDR malignant cells.

Original languageEnglish (US)
Pages (from-to)90-100
Number of pages11
JournalInternational Journal of Biochemistry and Molecular Biology
Volume1
Issue number1
StatePublished - Dec 1 2010

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Keywords

  • Apoptosis
  • Caspases
  • Death receptors
  • P-glycoprotein
  • TRAIL
  • TRAIL death receptor 5 (DR5)

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry

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