Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90.
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 EGFR, 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, 6β-acetonyl-22β-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 radiosensitizers, which can be used in combined radiotherapy.
Laboratory of Modulation of Radiobiological Responses, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul 139-706, Republic of Korea.
Ji-Hyun
JH
Lee
Kyu Jin
KJ
Choi
Woo Duck
WD
Seo
Soon Young
SY
Jang
Mira
M
Kim
Byong Won
BW
Lee
Jun Young
JY
Kim
Seongman
S
Kang
Ki Hun
KH
Park
Yun-Sil
YS
Lee
Sangwoo
S
Bae
D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D005720:Gamma Rays; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000077022:Survivin; D014315:Triterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D066246:ErbB Receptors; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D053978:Pentacyclic Triterpenes; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077022:Survivin; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; C107489:BIRC5 protein, human; C495901:TP53 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C050414:celastrol