Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90

Abstract

The radiosensitizing activity of celastrol, a quinone methide triterpene was examined. We found that celastrol treatment of the NCI-H460 lung cancer cell line increased radiation-induced cell killing. The increased radiosensitivity was correlated with decreased levels of Hsp90 clients, such as EGER, ErbB2 and survivin as well as with increased p53 expression. Celastrol inhibited the ATP-binding activity of Hsp90. Furthermore, celastrol treatment dissociated an Hsp90 client protein, EGFR, and this in turn resulted in degradation of the client protein. These results were not observed with another structurally similar triterpenoid, 6 beta-acetonyl-22 beta-hydroxytingenol (TG), suggesting that a specific structural feature of the triterpenoid is required for radiosensitization. Moreover celastrol treatment increased p53 levels by phosphorylating Ser15 and Ser20 residues as well as by inhibiting its proteasomal degradation. Celastrol may be considered an effective radiosensitizer acting as an inhibitor of Hsp90 and a p53 activator. The two activities could be applicable to a broad range of cancer cells with either wild-type or mutant p53 because either activity could be effective for the enhancement of radiation cell killing. Further analysis with other triterpenoids should identify the functional moiety of the structure and additional candidates for effective racliosensitizers, which can be used in combined radiotherapy.