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ABSTRACT: Tumor cells accumulate high level of reactive oxygen species (ROS) because they are metabolically more active than healthy cells. Elevated ROS levels increase tumorigenecity but also render cancer cells more vulnerable to oxidative stress than healthy cells. The oncogenic transcription factor Forkhead Box M1 (FOXM1), which is overexpressed in a wide range of human cancers, was reported to protect cancer cells from the adverse effects of oxidative stress by up-regulating the expression of scavenger enzymes. We therefore hypothesized that the combination of FOXM1 ablation and ROS inducers could selectively eradicate cancer cells. We show that RNA interface-mediated knockdown of FOXM1 further elevates intracellular ROS levels and increases sensitivity of cancer cells to ROS-mediated cell death after treatment with ROS inducers. We also report that the combination of ROS inducers with FOXM1/proteasome inhibitors induces robust apoptosis in different human cancer cells. In addition, we report evidence that the FOXM1/proteasome inhibitor bortezomib in combination with the ROS inducer β-phenylethyl isothiocyanate efficiently inhibits the growth of breast tumor xenografts in nude mice. We conclude that the combination of ROS inducers and FOXM1 inhibitors could be used as a therapeutic strategy to selectively eliminate cancer cells.
American Journal Of Pathology 05/2013; · 4.89 Impact Factor
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ABSTRACT: FOXM1 is an oncogenic transcription factor of the Forkhead family and it has a well-defined role in cell proliferation and cell-cycle progression. Expression of FOXM1 is excluded in quiescent or differentiated cells, but its level is highly elevated in proliferating and malignant cells. Overexpression of FOXM1 has been reported in more than 20 types of human cancer. In recent years, FOXM1 has been implicated in diverse cellular processes and also a growing body of experimental data has underlined the relevance of FOXM1 in tumorigenesis. Although FOXM1 is under the control of three major tumor suppressors (RB, p53, and p19(ARF)), it is still active in the majority of human cancers. The oncogenic potential of FOXM1 is mainly based on its ability to transcriptionally activate genes that are involved in different facets of cancer development. In this review, the contribution of FOXM1 to each of the hallmarks of cancer will be summarized and discussed. Mol Cancer Ther; 12(3); 1-10. ©2012 AACR.
Molecular Cancer Therapeutics 02/2013; · 5.23 Impact Factor
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ABSTRACT: Oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers. In addition, FOXM1 has been implicated in cell migration, invasion, angiogenesis and metastasis. The important role of FOXM1 in cancer affirms its significance for therapeutic intervention. Current data suggest that targeting FOXM1 in mono- or combination therapy may have promising therapeutic benefits for the treatment of cancer. However, challenges with the delivery of anti-FOXM1 siRNA to tumors and the absence of small molecules, which specifically inhibit FOXM1, are delaying the development of FOXM1 inhibitors as feasible anticancer drugs. In this review, we describe and summarize the efforts that have been made to target FOXM1 in cancer and the consequences of FOXM1 suppression in human cancer cells.
Biochemical pharmacology 10/2012; · 4.25 Impact Factor
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ABSTRACT: Irradiation and DNA-damaging chemotherapeutic agents are commonly used in anticancer treatments. Following DNA damage FOXM1 protein levels are often elevated. In this study, we sought to investigate the potential role of FOXM1 in programmed cell death induced by DNA-damage. Human cancer cells after FOXM1 suppression were subjected to doxorubicin or γ-irradiation treatment. Our findings indicate that FOXM1 downregulation by stable or transient knockdown using RNAi or by treatment with proteasome inhibitors that target FOXM1 strongly sensitized human cancer cells of different origin to DNA-damage-induced apoptosis. We showed that FOXM1 suppresses the activation of pro-apoptotic JNK and positively regulates anti-apoptotic Bcl-2, suggesting that JNK activation and Bcl-2 down-regulation could mediate sensitivity to DNA-damaging agent-induced apoptosis after targeting FOXM1. Since FOXM1 is widely expressed in human cancers, our data further support the fact that it is a valid target for combinatorial anticancer therapy.
PLoS ONE 01/2012; 7(2):e31761. · 4.09 Impact Factor
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ABSTRACT: Using mass spectrometric analysis we found that oncogenic transcription factor FOXM1 that is overexpressed in a majority of human cancers interacts with multifunctional protein NPM, which is also overexpressed in a variety of human tumors. Coimmunoprecipitation and glutathione S-transferase pull-down experiments demonstrated that NPM forms a complex with FOXM1 and also identified the regions responsible for their interaction. Immunofluorescence microscopy confirmed the interaction between FOXM1 and NPM in cancer and immortal cells. Furthermore, knockdown of NPM in immortal and cancer cells led to significant down-regulation of FOXM1 similar to its levels in normal cells, suggesting that NPM might modulate FOXM1 level. In addition, in OCI/AML3 leukemia cells where mutant NPM is localized in the cytoplasm we found that typically nuclear FOXM1 was predominantly co-localized with NPM in the cytoplasm, while NPM knockdown led to the disappearance of FOXM1 from the cytoplasm, suggesting that NPM may also determine intracellular localization of FOXM1. Knockdown of FOXM1 or NPM in MIA PaCa-2 pancreatic cancer cells inhibited anchorage-dependent and independent growth in cell culture, and tumor growth in nude mice. In addition, over-expression of FOXM1 reversed the effect of NPM knockdown in vitro. Our data suggest that in cancer cells NPM interacts with FOXM1 and their interaction is required for sustaining the level and localization of FOXM1. Targeting the interaction between FOXM1 and NPM by peptides or small molecules may represent a novel therapeutic strategy against cancer.
Journal of Biological Chemistry 12/2011; 286(48):41425-33. · 4.77 Impact Factor
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Cell cycle (Georgetown, Tex.) 03/2010; 9(6):1214-7. · 5.36 Impact Factor
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ABSTRACT: The Forkhead box M1 (FoxM1) oncogenic transcription factor is overexpressed in a majority of human tumors. p53 is a transcription factor and a major tumor suppressor that is mutated in 50% of human cancers. In this study, we compared the levels of FoxM1 in normal BJ human fibroblasts, BJ fibroblasts with p53 knockdown and corresponding BJ immortal/oncogenic cell lines with inactivated p53. We found that partial deletion or inactivation of p53 in these cells leads to upregulation of FoxM1 expression. Similarly, p53 knockdown in several human cancer cell lines with wt-p53 led to upregulation of FoxM1 mRNA and protein expression, while induction of p53 by DNA-damage led to downregulation of FoxM1. These data suggest that p53 negatively regulates FoxM1 expression and therefore inactivation of p53 in tumors could partially explain the phenomenon of FoxM1 overexpression in human cancers.
Cell cycle (Georgetown, Tex.) 10/2009; 8(20):3425-7. · 5.36 Impact Factor
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ABSTRACT: Cancer cells are generally more sensitive to anticancer drugs than normal cells. This provides the rationale for using anticancer drugs specifically against tumor cells, but the explanation for the specificity is often elusive. In this study, we compared the sensitivity of normal BJ human fibroblasts, BJ fibroblasts with p53 knockdown and corresponding BJ immortal/oncogenic cell lines with inactivated p53 to anticancer drug-induced apoptosis. We found that only normal cells that have wild-type p53 were resistant to the thiazole antibiotic, thiostrepton, suggesting that p53 plays an antiapoptotic role in normal cells. In this case p53 status, but not the transformation of cells per se determines their sensitivity to thiostrepton and possibly to other anticancer drugs. Since p53 is mutated in 50% of human cancers, thiostrepton may selectively kill cancer, but not normal cells. These data imply that wild-type p53 can protect normal cells from anticancer drug-induced cell death and its mutations may sensitize cancer cells to anti-neoplastic agents.
Cell cycle (Georgetown, Tex.) 10/2009; 8(17):2850-1. · 5.36 Impact Factor
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ABSTRACT: Oncogenic transcription factor FoxM1 represents an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tumors. Previously, we identified the thiazole antibiotics as potent inhibitors of FoxM1. Surprisingly, investigation of the mechanism of action of FoxM1 inhibitors revealed a novel mode of positive auto-regulation of FoxM1.
Cell cycle (Georgetown, Tex.) 07/2009; 8(12):1966-7. · 5.36 Impact Factor
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ABSTRACT: 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.
PLoS ONE 02/2009; 4(8):e6593. · 4.09 Impact Factor
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ABSTRACT: Forkhead box M1 (FoxM1) oncogenic transcription factor represents an attractive therapeutic target in the fight against cancer, because it is overexpressed in a majority of human tumors. Recently, using a cell-based assay system we identified thiazole antibiotic Siomycin A as an inhibitor of FoxM1 transcriptional activity. Here, we report that structurally similar thiazole antibiotic, thiostrepton also inhibits the transcriptional activity of FoxM1. Furthermore, we found that these thiopeptides did not inhibit the transcriptional activity of other members of the Forkhead family or some non-related transcription factors. Further experiments revealed that thiazole antibiotics also inhibit FoxM1 expression, but not the expression of other members of the Forkhead box family. In addition, we found that the thiazole antibiotics efficiently inhibited the growth and induced potent apoptosis in human cancer cell lines of different origin. Thiopeptide-induced apoptosis correlated with the suppression of FoxM1 expression, while overexpression of FoxM1 partially protected cancer cells from the thiazole antibiotic-mediated cell death. These data suggest that Siomycin A and thiostrepton may specifically target FoxM1 to induce apoptosis in cancer cells and FoxM1 inhibitors/thiazole antibiotics could be potentially developed as novel anticancer drugs against human neoplasia.
PLoS ONE 02/2009; 4(5):e5592. · 4.09 Impact Factor
