Abstract
BackgroundBecause 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.ResultsCelastrol 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.ConclusionsOur 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.
Highlights
Because some of heat shock protein 90's (HSP90) clients are key cell cycle regulators, HSP90 inhibition can affect the cell cycle
Antiproliferative effects of celastrol U937 cellular numbers were determined by flow cytometric (FCM) based on a modified one-tube platform, which can accurately count the number of total, living, and dead cells in a sample [19,20]
A dose-driven rise in apoptotic rates at doses above 1000 nM was revealed by flow cytometric (FCM) analysis of Annexin V/Propidium iodide (PI) stained cells (Figure 1B and 1C)
Summary
Because some of heat shock protein 90's (HSP90) clients are key cell cycle regulators, HSP90 inhibition can affect the cell cycle. The harsh environmental conditions found in tumors, such as hypoxia and low pH, as well as outside factors, such as poor nutrition, tend to destabilize proteins and further their dependence on HSP90. This hypothesis is supported by the higher HSP90 levels found in tumor cells, which can comprise as much as 4-6% of cellular proteins in contrast to the 1-2% seen in normal cells [3,4]. When used as a single agent or in combination with chemotherapy, HSP90 inhibitors have shown anti-tumor effects in cellular studies, animal model studies, and clinical evaluations [5,6,7]. It is too early for many of these inhibitors or their deriva-
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