Abstract
Celastrol, a novel HSP90 inhibitor, has recently attracted much attention due to its potential in multiple applications, such as anti-inflammation use, degenerative neuron disease relief, and tumor management. At present, the studies in celastrol's effects on HSP90's clients have focused on the kinase sub-population, while another key sub-population, nuclear transcription factors (TFs), is not being well-explored. In this study, we observe the effects of celastrol on 18 TFs (belonging to HSP90 clients) in three human cell lines: MCF-7 (breast cancer), HepG2 (hepatoma), and THP-1 (monocytic leukemia). The results show that at least half of the detectable TFs were affected by celastrol, though the effect patterns varied with cell type and dosage. Bi-directional regulations of some TFs were identified, a phenomenon not yet seen with other HSP90 inhibitors. Celastrol's capability to affect multiple TFs was consistent with its altering HSP90/TFs interactions and disrupting HSP90/Hop interaction, in addition to the reported damaging HSP90/Cdc37 interaction. This work confirms, for the first time, that celastrol has broad effects on TFs belonging to HSP90's clients, casts new light on understanding these reported actions, and suggests new possible applications for celastrol, such as diabetes management.
Similar content being viewed by others
References
Allison AC, Cacabelos R, Lombardi VR, Alvarez XA, Vigo C (2001) Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 25:1341–1357
Chadli A, Felts SJ, Wang Q, Sullivan WP, Botuyan MV, Fauq A, Ramirez-Alvarado M, Mer G (2010) Celastrol inhibits Hsp90 chaperoning of steroid receptors by inducing fibrillization of the Co-chaperone p23. J Biol Chem 285:4224–4231
Chow AM, Brown IR (2007) Induction of heat shock proteins in differentiated human and rodent neurons by celastrol. Cell Stress Chaperones 12:237–244
Dai Y, DeSano JT, Meng Y, Ji Q, Ljungman M, Lawrence TS, Xu L (2009) Celastrol potentiates radiotherapy by impairment of DNA damage processing in human prostate cancer. Int J Radiat Oncol Biol Phys 74:1217–1225
Faust K, Gehrke S, Yang Y, Yang L, Beal MF, Lu B (2009) Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease. BMC Neurosci 10:109
Gao J, He J, Zhai Y, Wada T, Xie W (2009) The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem 284:25984–25992
Ge P, Ji X, Ding Y, Wang X, Fu S, Meng F, Jin X, Ling F, Luo Y (2010) Celastrol causes apoptosis and cell cycle arrest in rat glioma cells. Neurol Res 32:94–100
Hassane DC, Guzman ML, Corbett C, Li X, Abboud R, Young F, Liesveld JL, Carroll M, Jordan CT (2008) Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood 111:5654–5662
He D, Xu Q, Yan M, Zhang P, Zhou X, Zhang Z, Duan W, Zhong L, Ye D, Chen W (2009a) The NF–kappa B inhibitor, celastrol, could enhance the anti-cancer effect of gambogic acid on oral squamous cell carcinoma. BMC Cancer 9:343
He MF, Liu L, Ge W, Shaw PC, Jiang R, Wu LW, But PP (2009b) Antiangiogenic activity of Tripterygium wilfordii and its terpenoids. J Ethnopharmacol 121:61–68
Hieronymus H, Lamb J, Ross KN, Peng XP, Clement C, Rodina A, Nieto M, Du J, Stegmaier K, Raj SM, Maloney KN, Clardy J, Hahn WC, Chiosis G, Golub TR (2006) Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell 10:321–330
Huang FC, Chan WK, Moriarty KJ, Zhang DC, Chang MN, He W, Yu KT, Zilberstein A (1998) Novel cytokine release inhibitors. Part I: triterpenes. Bioorg Med Chem Lett 8:1883–1886
Jung HW, Chung YS, Kim YS, Park YK (2007) Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-kappaB in LPS-stimulated BV-2 microglial cells. Exp Mol Med 39:715–721
Kiaei M, Kipiani K, Petri S, Chen J, Calingasan NY, Beal MF (2005) Celastrol blocks neuronal cell death and extends life in transgenic mouse model of amyotrophic lateral sclerosis. Neurodegener Dis 2:246–254
Kim DH, Shin EK, Kim YH, Lee BW, Jun JG, Park JH, Kim JK (2009a) Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regelii. Eur J Clin Invest 39:819–827
Kim DY, Park JW, Jeoung D, Ro JY (2009b) Celastrol suppresses allergen-induced airway inflammation in a mouse allergic asthma model. Eur J Pharmacol 612:98–105
Kim Y, Kim K, Lee H, Han S, Lee YS, Choe J, Kim YM, Hahn JH, Ro JY, Jeoung D (2009c) Celastrol binds to ERK and inhibits FcepsilonRI signaling to exert an anti-allergic effect. Eur J Pharmacol 612:131–142
Lee JH, Koo TH, Yoon H, Jung HS, Jin HZ, Lee K, Hong YS, Lee JJ (2006) Inhibition of NF-kappa B activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoid. Biochem Pharmacol 72:1311–1321
Li Y, Zhang T, Schwartz SJ, Sun D (2009) New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Updat 12:17–27
Morimoto RI (1998) Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev 12:3788–3796
Nagase M, Oto J, Sugiyama S, Yube K, Takaishi Y, Sakato N (2003) Apoptosis induction in HL-60 cells and inhibition of topoisomerase II by triterpene celastrol. Biosci Biotechnol Biochem 67:1883–1887
Pang X, Yi Z, Zhang J, Lu B, Sung B, Qu W, Aggarwal BB, Liu M (2010) Celastrol suppresses angiogenesis-mediated tumor growth through inhibition of AKT/mammalian target of rapamycin pathway. Cancer Res 70:1951–1959
Pinna GF, Fiorucci M, Reimund JM, Taquet N, Arondel Y, Muller CD (2004) Celastrol inhibits pro-inflammatory cytokine secretion in Crohn's disease biopsies. Biochem Biophys Res Commun 322:778–786
Salminen A, Lehtonen M, Paimela T, Kaarniranta K (2010) Celastrol: molecular targets of Thunder God Vine. Biochem Biophys Res Commun 394:439–442
Sethi G, Ahn KS, Pandey MK, Aggarwal BB (2007) Celastrol, a novel triterpene, potentiates TNF-induced apoptosis and suppresses invasion of tumor cells by inhibiting NF-kappaB-regulated gene products and TAK1-mediated NF-kappaB activation. Blood 109:2727–2735
Sreeramulu S, Gande SL, Gobel M, Schwalbe H (2009) Molecular mechanism of inhibition of the human protein complex Hsp90-Cdc37, a kinome chaperone-cochaperone, by triterpene celastrol. Angew Chem Int Ed Engl 48:5853–5855
Sung B, Park B, Yadav VR, Aggarwal BB (2010) Celastrol, a triterpene, enhances TRAIL-induced apoptosis through the down-regulation of cell survival proteins and up-regulation of death receptors. J Biol Chem 285:11498–11507
Trott A, West JD, Klaic L, Westerheide SD, Silverman RB, Morimoto RI, Morano KA (2008) Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. Mol Biol Cell 19:1104–1112
Westerheide SD, Bosman JD, Mbadugha BN, Kawahara TL, Matsumoto G, Kim S, Gu W, Devlin JP, Silverman RB, Morimoto RI (2004) Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem 279:56053–56060
Yang H, Chen D, Cui QC, Yuan X, Dou QP (2006) Celastrol, a triterpene extracted from the Chinese "Thunder of God Vine," is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res 66:4758–4765
Zhang DH, Marconi A, Xu LM, Yang CX, Sun GW, Feng XL, Ling CQ, Qin WZ, Uzan G, d'Alessio P (2006) Tripterine inhibits the expression of adhesion molecules in activated endothelial cells. J Leukoc Biol 80:309–319
Zhang T, Hamza A, Cao X, Wang B, Yu S, Zhan CG, Sun D (2008) A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells. Mol Cancer Ther 7:162–170
Zhang T, Li Y, Yu Y, Zou P, Jiang Y, Sun D (2009) Characterization of celastrol to inhibit hsp90 and cdc37 interaction. J Biol Chem 284:35381–35389
Acknowledgements
This work is supported by Pujiang Overseas Return Talent Project of Shanghai Government (07pj14075).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary materials
Below is the link to the electronic supplementary material.
ESM 1
(DOC 176 kb)
Rights and permissions
About this article
Cite this article
Zhang, D., Xu, L., Cao, F. et al. Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way. Cell Stress and Chaperones 15, 939–946 (2010). https://doi.org/10.1007/s12192-010-0202-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12192-010-0202-1