Identification of a Chemical Inhibitor of the Oncogenic Transcription Factor Forkhead Box M1

Radhakrishnan, Senthil K.; Bhat, Uppoor G.; Hughes, Douglas E.; Wang, I‐Ching; Costa, Robert H.; Gartel, Andrei L.

doi:10.1158/0008-5472.can-06-1576

Cited by 219 publications

(246 citation statements)

References 27 publications

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“…Similarly in our study, we investigated the effects of dexamethasone and siomycin A on T-ALL cells and found that dexamethasone and siomycin A alone or in combination caused a significant reduction in gene expression levels of FoxM1 in a dose-dependent manner. Besides causing down-regulation of FoxM1, siomycin A has also been known to reduce the mRNA and protein levels of this transcription factor [22][23][24].…”

Section: Discussionmentioning

confidence: 99%

“…Siomycin A was identified as a strong proapoptotic compound in epithelial cells and also as a potential anticancer drug that causes apoptosis and induces lysosomal membrane permeabilisation [21]. Siomycin A has been shown to downregulate the transcriptional activity and also the protein and mRNA levels of FoxM1 in human cancer cell lines [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

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Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line

et al. 2015

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The Forkhead box protein M1 (FoxM1) is an important transcription factor having significant roles in various cellular events. FoxM1 overexpression has been reported to be related with many types of cancer. However, it is not known whether it contributes to oncogenesis of acute lymphoblastic leukemia. Siomycin A, a thiazol antibiotic, is known to inhibit FoxM1 transcriptional activity. In this study, we aimed to determine gene expression levels of FoxM1 in Jurkat cells (T-cell acute lymphoblastic leukemia cell line) and therapeutic potential of targeting FoxM1 by siomycin A alone and in combination with dexamethasone which improves the survival of children with T-cell acute lymphoblastic leukemia (ALL). We also examined the molecular mechanisms of siomycin A and dexamethasone-induced cell death in Jurkat cells. We demonstrated that FoxM1 mRNA is highly expressed in Jurkat cells. Dexamethasone and siomycin A caused a significant reduction in gene expression levels of FoxM1 in Jurkat cells. Targeting FoxM1 by siomycin A and dexamethasone caused a significant decrease in T-ALL cell line proliferation through induction of G1 cell cycle arrest. All these findings suggest a possible role of FoxM1 in T-cell ALL pathogenesis and represent FoxM1 as an attractive target for T-cell ALL therapy. © 2014 Elsevier Ltd.Dokuz Eylul University Scientific Research Projects Coordination Unit (99.3456.23

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line

et al. 2015

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“…FOXM1 has been reported previously to be a valid therapeutic target in cancer (25); the use of a cell-penetrating ARF peptide inhibitor of FOXM1 has been shown to selectively induce apoptosis in human hepatocellular carcinoma cell lines and mouse models (14). In addition, a related antibiotic thiazole compound, siomycin A, has been reported to downregulate the transcriptional activity and expression of FOXM1 (26). It is interesting to note that Radhakrishnan et al have shown that overexpression of wild-type FOXM1 is sufficient to block the antiproliferative effects of thiostrepton, whereas we found here that only expression of a constitutively active DN-FOXM1, but not the wild-type FOXM1, can rescue cells from the antiproliferative effects of thiostrepton.…”

Section: Discussionmentioning

confidence: 99%

Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression

Kwok

Myatt

Marson

et al. 2008

Molecular Cancer Therapeutics

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Elevated expression or activity of the transcription factor forkhead box M1 (FOXM1) is associated with the development and progression of many malignancies, including breast cancer. In this study, we show that the thiazole antibiotic thiostrepton selectively induces cell cycle arrest and cell death in breast cancer cells through down-regulating FOXM1 expression. Crucially, our data show that thiostrepton treatment reduced FOXM1 expression in a time-and dose-dependent manner, independent of de novo protein synthesis and predominantly at transcriptional and gene promoter levels. Our results indicate that thiostrepton can induce cell death through caspase-dependent intrinsic and extrinsic apoptotic pathways as well as through caspase-independent death mechanisms, as observed in MCF-7 cells, which are deficient of caspase-3 and caspase-7. Cell cycle analysis showed that thiostrepton induced cell cycle arrest at G 1 and S phases and cell death, concomitant with FOXM1 repression in breast cancer cells. Furthermore, thiostrepton also shows efficacy in repressing breast cancer cell migration, metastasis, and transformation, which are all downstream functional attributes of FOXM1. We also show that overexpression of a constitutively active FOXM1 mutant, #N-FOXM1, can abrogate the antiproliferative effects of thiostrepton. Interestingly, thiostrepton has no affect on FOXM1 expression and proliferation of the untransformed MCF-10A breast epithelial cells. Collectively, our data show that FOXM1 is one of the primary cellular targets of thiostrepton in breast cancer cells and that thiostrepton may represent a novel lead compound for targeted therapy of breast cancer with minimal toxicity against noncancer cells.

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“…Amsacrine also further increased GFP-LC3 puncta in the presence of BafA1 (Supplementary Figure 2C and D). By contrast, siomycin-A (which is a putative FoxM1 inhibitor) (Radhakrishnan et al, 2006) failed to induce autophagy and rather inhibited fusion between GFP-LC3 þ and LAMP2 þ vacuoles, indicating that it prevented the fusion between autophagosomes and lysosomes (which is also inhibited by the vacuolar ATPase inhibitor, BafA1) (Supplementary Figure 2A-D). These results underscore the necessity of carefully measuring autophagic flux to distinguish inducers of autophagy from blockers of the last steps of autophagic turnover.…”

Section: A Chemical Compound Screen For Simultaneous Detection Of Autmentioning

confidence: 99%

Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

et al. 2011

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To address the question of whether established or experimental anticancer chemotherapeutics can exert their cytotoxic effects by autophagy, we performed a highcontent screen on a set of cytotoxic agents. We simultaneously determined parameters of autophagy, apoptosis and necrosis on cells exposed to B1400 compounds. Many agents induced a 'pure' autophagic, apoptotic or necrotic phenotype, whereas less than 100 simultaneously induced autophagy, apoptosis and necrosis. A systematic analysis of the autophagic flux induced by the most potent 80 inducers of GFP-LC3 puncta among the NCI panel agents showed that 59 among them truly induced autophagy. The remaining 21 compounds were potent inducers of apoptosis or necrosis, yet failed to stimulate an autophagic flux, which were characterized as microtubule inhibitors. Knockdown of ATG7 was efficient in preventing GFP-LC3 puncta, yet failed to attenuate cell death by the agents that induce GFP-LC3 puncta. Thus there is not a single compound that would induce cell death by autophagy in our screening, underscoring the idea that cell death is rarely, if ever, executed by autophagy in human cells.

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Identification of a Chemical Inhibitor of the Oncogenic Transcription Factor Forkhead Box M1

Cited by 219 publications

References 27 publications

Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line

Targeting FoxM1 transcription factor in T-cell acute lymphoblastic leukemia cell line

Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression

Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

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