Celastrol regulates multiple nuclear transcription factors belonging to HSP90's clients in a dose- and cell type-dependent way

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.

[1]  M. Ramirez-Alvarado,et al.  Celastrol Inhibits Hsp90 Chaperoning of Steroid Receptors by Inducing Fibrillization of the Co-chaperone p23* , 2009, The Journal of Biological Chemistry.

[2]  Tao Zhang,et al.  A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells , 2008, Molecular Cancer Therapeutics.

[3]  Yong-Ki Park,et al.  Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-κB in LPS-stimulated BV-2 microglial cells , 2007, Experimental & Molecular Medicine.

[4]  G. Uzan,et al.  Tripterine inhibits the expression of adhesion molecules in activated endothelial cells , 2006, Journal of leukocyte biology.

[5]  M. Beal,et al.  Celastrol Blocks Neuronal Cell Death and Extends Life in Transgenic Mouse Model of Amyotrophic Lateral Sclerosis , 2006, Neurodegenerative Diseases.

[6]  T. Lawrence,et al.  Celastrol potentiates radiotherapy by impairment of DNA damage processing in human prostate cancer. , 2009, International journal of radiation oncology, biology, physics.

[7]  A. Allison,et al.  Celastrol, a potent antioxidant and anti-inflammatory drug, as a possible treatment for Alzheimer's disease , 2001, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[8]  A. Chow,et al.  Induction of heat shock proteins in differentiated human and rodent neurons by celastrol , 2007, Cell stress & chaperones.

[9]  B. Aggarwal,et al.  Celastrol, a Triterpene, Enhances TRAIL-induced Apoptosis through the Down-regulation of Cell Survival Proteins and Up-regulation of Death Receptors* , 2010, The Journal of Biological Chemistry.

[10]  W. Ge,et al.  Antiangiogenic activity of Tripterygium wilfordii and its terpenoids. , 2009, Journal of ethnopharmacology.

[11]  S. Westerheide,et al.  Celastrols as Inducers of the Heat Shock Response and Cytoprotection*[boxs] , 2004, Journal of Biological Chemistry.

[12]  B. Aggarwal,et al.  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. , 2007, Blood.

[13]  Yun‐Sil Lee,et al.  Celastrol binds to ERK and inhibits FcepsilonRI signaling to exert an anti-allergic effect. , 2009, European journal of pharmacology.

[14]  Yonggong Zhai,et al.  The Constitutive Androstane Receptor Is an Anti-obesity Nuclear Receptor That Improves Insulin Sensitivity* , 2009, The Journal of Biological Chemistry.

[15]  Young-Soo Hong,et al.  Inhibition of NF-kappa B activation through targeting I kappa B kinase by celastrol, a quinone methide triterpenoid. , 2006, Biochemical pharmacology.

[16]  Y. H. Kim,et al.  Suppression of inflammatory responses by celastrol, a quinone methide triterpenoid isolated from Celastrus regelii , 2009, European journal of clinical investigation.

[17]  Monica L Guzman,et al.  Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. , 2008, Blood.

[18]  A. Zilberstein,et al.  Novel cytokine release inhibitors. Part I: Triterpenes. , 1998, Bioorganic & medicinal chemistry letters.

[19]  J. Reimund,et al.  Celastrol inhibits pro-inflammatory cytokine secretion in Crohn's disease biopsies. , 2004, Biochemical and biophysical research communications.

[20]  T. Golub,et al.  Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. , 2006, Cancer cell.

[21]  X. Ji,et al.  Celastrol causes apoptosis and cell cycle arrest in rat glioma cells , 2010, Neurological research.

[22]  S. Westerheide,et al.  Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. , 2007, Molecular biology of the cell.

[23]  Tao Zhang,et al.  New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. , 2009, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[24]  N. Sakato,et al.  Apoptosis Induction in HL-60 Cells and Inhibition of Topoisomerase II by Triterpene Celastrol , 2003, Bioscience, biotechnology, and biochemistry.

[25]  Young-Soo Hong,et al.  Inhibition of NF-κB activation through targeting IκB kinase by celastrol, a quinone methide triterpenoid , 2006 .

[26]  R. Morimoto,et al.  Regulation of the Heat Shock Transcriptional Response: Cross Talk between a Family of Heat Shock Factors, Molecular Chaperones, and Negative Regulators the Heat Shock Factor Family: Redundancy and Specialization , 2022 .

[27]  Di Chen,et al.  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. , 2006, Cancer research.

[28]  A. Salminen,et al.  Celastrol: Molecular targets of Thunder God Vine. , 2010, Biochemical and biophysical research communications.

[29]  M. Beal,et al.  Neuroprotective effects of compounds with antioxidant and anti-inflammatory properties in a Drosophila model of Parkinson's disease , 2009, BMC Neuroscience.

[30]  D. Jeoung,et al.  Celastrol suppresses allergen-induced airway inflammation in a mouse allergic asthma model. , 2009, European journal of pharmacology.

[31]  Tao Zhang,et al.  Characterization of Celastrol to Inhibit Hsp90 and Cdc37 Interaction* , 2009, The Journal of Biological Chemistry.

[32]  Mingyao Liu,et al.  Celastrol suppresses angiogenesis-mediated tumor growth through inhibition of AKT/mammalian target of rapamycin pathway. , 2010, Cancer research.

[33]  H. Schwalbe,et al.  Molecular mechanism of inhibition of the human protein complex Hsp90-Cdc37, a kinome chaperone-cochaperone, by triterpene celastrol. , 2009, Angewandte Chemie.

[34]  Ming Yan,et al.  The NF-kappa B inhibitor, celastrol, could enhance the anti-cancer effect of gambogic acid on oral squamous cell carcinoma , 2009, BMC Cancer.