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

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J. Biol. Chem, 10.1074/jbc.M802511200

ABT-737 induces expression of the death receptor 5 and sensitizes human cancer

cells to TRAIL-induced apoptosis

Jin H. Song, Karthikeyan Kandasamy, and S. Kraft

Hollings Cancer Center, Medical University of South Carolina, ton, SC

29425

Corresponding Author: kraft@...

Because Bcl-2 family members inhibit the ability of 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 DISC

components were evaluated. Treatment with ABT-737 did not change the levels of

c-FLIP, FADD, and caspase-8, but upregulated 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-B

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-B 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.