Int J Biochem Mol Biol 2010;1(1):90-100
Original Article
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
Department of Pharmacology and Toxicology and Indiana University Simon Cancer Center, 980 W. Walnut Street, Indianapolis, IN 46202, USA.
Received June 29, 2010; accepted July, 2010; available online July, 2010; published August 1, 2010
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) 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). TRAIL-triggered 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-gp-overexpressing 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.
(IJBMB1006001).
Keywords: TRAIL, P-glycoprotein, TRAIL death receptor 5 (DR5), apoptosis, caspases, death receptors
Full Text PDF
Address all correspondence to:
Ahmad R. Safa, PhD
Department of Pharmacology and Toxicology and Indiana University Simon Cancer Center
980 W. Walnut Street, R3-C524
Indianapolis, IN 46202
Tel: (317) 278-4952; Fax: (317) 274-8046
E-mail: asafa@iupui.edu
Original Article
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
Department of Pharmacology and Toxicology and Indiana University Simon Cancer Center, 980 W. Walnut Street, Indianapolis, IN 46202, USA.
Received June 29, 2010; accepted July, 2010; available online July, 2010; published August 1, 2010
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) 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). TRAIL-triggered 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-gp-overexpressing 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.
(IJBMB1006001).
Keywords: TRAIL, P-glycoprotein, TRAIL death receptor 5 (DR5), apoptosis, caspases, death receptors
Full Text PDF
Address all correspondence to:
Ahmad R. Safa, PhD
Department of Pharmacology and Toxicology and Indiana University Simon Cancer Center
980 W. Walnut Street, R3-C524
Indianapolis, IN 46202
Tel: (317) 278-4952; Fax: (317) 274-8046
E-mail: asafa@iupui.edu
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