Blocking NF-κB and Akt by Hsp90 inhibition sensitizes Smac mimetic compound 3-induced extrinsic apoptosis pathway and results in synergistic cancer cell death.

ABSTRACT: NF-κB and Akt are two main cell survival pathways that attenuate the anticancer efficacy of therapeutics. Our previous studies demonstrated that the Smac mimetic compound 3 (SMC3) specifically suppresses c-IAP1 and induces TNF-α autocrine to kill cancer cells. However, SMC3 also induces a cell survival signal through NF-κB activation. In this report, we further found that SMC3 potently activates Akt, which inhibits SMC3-induced cancer cell death. Strikingly, concurrent blocking NF-κB and Akt resulted in a significantly potentiated cytotoxicity. Because heat shock protein 90 (Hsp90) plays an important role in maintaining the integrity of both the NF-κB and Akt pathways in cancer cells, we examined if suppression of Hsp90 is able to potentiate SMC3-induced cancer cell death. The results show

SUBMITTER: Bai L 

PROVIDER: S-EPMC3079540 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature