HSP90 inhibitor, celastrol, arrests human monocytic leukemia cell U937 at G0/G1 in thiol-containing agents reversible way.
BACKGROUND
Because some of heat shock protein 90's (HSP90) clients are key cell cycle regulators, HSP90 inhibition can affect the cell cycle. Recently, celastrol is identified both as a novel inhibitor of HSP90 and as a potential anti-tumor agent. However, this agent's effects on the cell cycle are rarely investigated. In this study, we observed the effects of celastrol on the human monocytic leukemia cell line U937 cell cycle.


RESULTS
Celastrol affected the proliferation of U937 in a dose-dependent way, arresting the cell cycle at G0/G1 with 400 nM doses and triggering cell death with doses above 1000 nM. Cell cycle arrest was accompanied by inhibition of HSP90 ATPase activity and elevation in HSP70 levels (a biochemical hallmark of HSP90 inhibition), a reduction in Cyclin D1, Cdk4 and Cdk6 levels, and a disruption of the HSP90/Cdc37/Cdk4 complex. The observed effects of celastrol on the U937 cell cycle were thiol-related, firstly because the effects could be countered by pre-loading thiol-containing agents and secondly because celastrol and thiol-containing agents could react with each other to form new compounds.


CONCLUSIONS
Our results disclose a novel action of celastrol-- causing cell cycle arrest at G0/G1 phase based upon thiol-related HSP90 inhibition. Our work suggests celastrol's potential in tumor and monocyte-related disease management.
Peng
Bin
B
Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, 207 Ju Ye Road, Pudong New District, Shanghai, China.
Xu
Limin
L
Cao
Fanfan
F
Wei
Tingxuan
T
Yang
Chunxin
C
Uzan
Georges
G
Zhang
Denghai
D
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047468:Immunoprecipitation; D053978:Pentacyclic Triterpenes; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D020298:U937 Cells
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D053978:Pentacyclic Triterpenes; D013438:Sulfhydryl Compounds; D014315:Triterpenes; C050414:celastrol
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