FoxM1 Is a General Target for Proteasome Inhibitors

Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(8):e6593. DOI: 10.1371/journal.pone.0006593
Source: PubMed


Proteasome inhibitors are currently in the clinic or in clinical trials, but the mechanism of their anticancer activity is not completely understood. The oncogenic transcription factor FoxM1 is one of the most overexpressed genes in human tumors, while its expression is usually halted in normal non-proliferating cells. Previously, we established that thiazole antibiotics Siomycin A and thiostrepton inhibit FoxM1 and induce apoptosis in human cancer cells. Here, we report that Siomycin A and thiostrepton stabilize the expression of a variety of proteins, such as p21, Mcl-1, p53 and hdm-2 and also act as proteasome inhibitors in vitro. More importantly, we also found that well-known proteasome inhibitors such as MG115, MG132 and bortezomib inhibit FoxM1 transcriptional activity and FoxM1 expression. In addition, overexpression of FoxM1 specifically protects against bortezomib-, but not doxorubicin-induced apoptosis. These data suggest that negative regulation of FoxM1 by proteasome inhibitors is a general feature of these drugs and it may contribute to their anticancer properties.

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Available from: Andrei Gartel, Aug 14, 2014
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    • "We demonstrated that the anticancer activities of thiostrepton and Siomycin A are linked to their activity as proteasome inhibitors in human tumor cells [22]. We tested whether other known thiazole antibiotics such as berninamycin, micrococcin P1 and micrococcin P2, thiocillin, and YM-266183 (lacking the quinaldic acid ring B) [23] could demonstrate proteasome inhibitor activity. "
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    ABSTRACT: The oncogenic transcription factor FOXM1 is one of the key regulators of tumorigenesis. We found that FOXM1 upregulates its own transcription and its protein stability depends on its interaction with the chaperone nucleophosmin. We also determined that FOXM1 is negatively regulated by the tumor suppressor p53. We identified the thiazole antibiotics Siomycin A and thiostrepton as inhibitors of transcriptional activity and FOXM1 expression via proteasome inhibition. In addition, we found that all tested proteasome inhibitors target FOXM1. We showed synergy between thiostrepton and bortezomib in different human cancer cell lines and in vivo. We generated isogenic human cancer cell lines of different origin with wild-type p53 or p53 knockdown and we demonstrated that proteasome inhibitors induce p53-independent apoptosis in these cells. Using RNA-interference or proteasome inhibitors to inhibit FOXM1 we found that suppression of FOXM1 sensitized human cancer cells to apoptosis induced by DNA-damaging agents or oxidative stress. We encapsulated thiostrepton into micelle-nanoparticles and after injection we detected accumulation of nanoparticles in tumors and in the livers of treated mice. This treatment led to inhibition of human xenograft tumor growth in nude mice. Our data indicate that targeting FOXM1 increases apoptosis and inhibits tumor growth.
    06/2014; 2014:596528. DOI:10.1155/2014/596528
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    • "Among these mechanisms, up-regulation of Mcl-1 has often been implicated in proteasome inhibitor resistance [7], [9]. For example, administration of proteasome inhibitors (e.g., bortezomib) induce Mcl-1 accumulation by blocking its proteasomal degradation [64], thus limiting their anti-MM activity [7], [8]. Consistent with these findings, MM cells ectopically expressing Mcl-1 were highly resistant to bortezomib, while bortezomib-resistant MM cells (e.g., PS-R cells), which acquired resistance through continuous culture in progressively higher bortezomib concentrations, exhibited both Mcl-1 up-regulation and Bim down-regulation [20]. "
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    ABSTRACT: The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.
    PLoS ONE 03/2014; 9(3):e89064. DOI:10.1371/journal.pone.0089064 · 3.23 Impact Factor
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    • "Many thiopeptides exhibit potent activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus sp., and Clostridium difficile. Other thiopeptides inhibit the 20S proteasome, highlighting their potential as antitumor agents (Bhat et al., 2009). However, the poor solubility and pharmacological properties of thiopeptides have limited clinical progress and only derivatives of GE2270 have entered clinical trials for the topical treatment of acne or of C. difficileassociated diarrhea (Butler, 2005; Donadio et al., 2010; LaMarche et al., 2012). "
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    ABSTRACT: Thiopeptides are ribosomally synthesized, posttranslationally modified peptides with potent activity against Gram-positives. However, only GE2270 has yielded semisynthetic derivatives under clinical investigations. The pbt gene cluster from the GE2270 producer Planobispora rosea was successfully expressed in the genetically tractable Nonomuraea ATCC39727. Gene deletions established that PbtO, PbtM1, PbtM2, PbtM3, and PbtM4 are involved in regiospecific hydroxylation and methylations of GE2270, leading to the generation of various derivatives with altered decorations. Further deletions established that PbtH and PbtG1 are involved in C-terminal amide and oxazoline formation, respectively. Surprisingly, preventing either step resulted in the accumulation of linear precursors in which the pyridine-generated macrocycle failed to form, and only one of the pyridine-forming serine residues had been dehydrated. Often, these linear precursors present a shortened C terminus but retain the full set of methylation and hydroxylation decorations.
    Chemistry & biology 08/2013; 131(8). DOI:10.1016/j.chembiol.2013.07.005 · 6.65 Impact Factor
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