ABT-737 induces expression of the death receptor 5 and sensitizes human cancer cells to TRAIL-induced apoptosis

Jin H. Song, Karthikeyan Kandasamy, Andrew Kraft

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Because Bcl-2 family members inhibit the ability of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to induce apoptosis, we investigated whether ABT-737, a small molecule Bcl-2 inhibitor, enhances TRAIL killing. We demonstrate that a combination of ABT-737 and TRAIL induced significant cell death in multiple cancer types, including renal, prostate, and lung cancers, although each agent individually had little activity in these tumor cells. All of these cell lines expressed the Mcl-1 protein that is known to block the activity of ABT-737 and TRAIL but did not block the synergy between these agents. However, Bax-deficient cell lines, including DU145 and HCT116 cells and those cell lines expressing low levels of TRAIL receptor, were resistant to apoptosis induced by these agents. To understand how ABT-737 functions to markedly increase TRAIL sensitivity, the levels of specific death-inducing signaling complex components were evaluated. Treatment with ABT-737 did not change the levels of c-FLIP, FADD, and caspase-8 but up-regulated the levels of the TRAIL receptor DR5. DR5 up-regulation induced by ABT-737 treatment occurred through a transcriptional mechanism, and mutagenesis studies demonstrated that the NF-κB site found in the DR5 promoter was essential for the ability of ABT-737 to increase the levels of this mRNA. Using luciferase reporter plasmids, ABT-737 was shown to stimulate NF-κB activity. Together, these results demonstrate that the ability of ABT-737 and TRAIL to induce apoptosis is mediated through activation of both the extrinsic and intrinsic pathways. Combinations of ABT-737 and TRAIL can be exploited therapeutically where antiapoptotic Bcl-2 family members drive tumor cell resistance to current anticancer therapies.

Original languageEnglish (US)
Pages (from-to)25003-25013
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number36
DOIs
StatePublished - Sep 5 2008
Externally publishedYes

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TNF-Related Apoptosis-Inducing Ligand Receptors
Cells
Apoptosis
Neoplasms
Aptitude
Cell Line
Tumors
Death Domain Receptor Signaling Adaptor Proteins
ABT-737
HCT116 Cells
Mutagenesis
Caspase 8
Kidney Neoplasms
Cell death
Luciferases
Lung Neoplasms
Prostatic Neoplasms
Plasmids
Cell Death
Up-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

ABT-737 induces expression of the death receptor 5 and sensitizes human cancer cells to TRAIL-induced apoptosis. / Song, Jin H.; Kandasamy, Karthikeyan; Kraft, Andrew.

In: Journal of Biological Chemistry, Vol. 283, No. 36, 05.09.2008, p. 25003-25013.

Research output: Contribution to journalArticle

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