FOXM1 is a transcription factor of the Forkhead family that is required for cell proliferation of normal cells. However, FOXM1 is repeatedly overexpressed in a variety of human cancers, and it has ...been implicated in all major hallmarks of cancer delineated by Hanahan and Weinberg. It has been postulated that the oncogenic potential of FOXM1 is determined by its capacity to transactivate target genes that are implicated in different phases of cancer development. However, FOXM1 may also play an oncogenic role by interacting with other proteins, such as β-catenin or SMAD3 to induce oncogenic WNT and TGFβ signaling pathways, respectively. In this review, I will discuss the protein-protein interactions of FOXM1 that are critical for cancer development and may represent novel targets for anticancer drugs.
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NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as ...a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.
Introduction: FOXM1 is one of the most frequently overexpressed proteins in human solid cancers. Here, we discuss novel direct targets of FOXM1 as well as new pathways involving FOXM1, through which ...this protein exerts its oncogenic activity.
Areas covered: We give a detailed review of FOXM1 transcriptional targets involved in 16 different types of human cancer as published in the literature in the last 5 years. We also discuss a novel positive feedback loop between FOXM1 and AKT - both well-established master regulators of cancer.
Expert opinion: Despite the discovery of several FOXM1 inhibitors over the years (by our team and others), their therapeutic use is limited by their adverse off-target effects.
Newly-discovered proteins regulated by FOXM1 present a promising alternative approach to target its pro-cancer activity. In addition, targeting regulating proteins that take part in the positive feedback loop between FOXM1/AKT has the double advantage of suppressing both, and can lead to developing novel anti-cancer drugs.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
FOX(M1) news--it is cancer Halasi, Marianna; Gartel, Andrei L
Molecular cancer therapeutics,
03/2013, Letnik:
12, Številka:
3
Journal Article
Recenzirano
Odprti dostop
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.
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.
Celotno besedilo
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Targeting FOXM1 in cancer Halasi, Marianna; Gartel, Andrei L.
Biochemical pharmacology,
03/2013, Letnik:
85, Številka:
5
Journal Article
Recenzirano
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.
Forkhead box (FOX) protein M1 (FOXM1) is a critical proliferation-associated transcription factor (TF) that is aberrantly overexpressed in the majority of human cancers and has also been implicated ...in poor prognosis. A comprehensive understanding of various aspects of this molecule has revealed its role in, cell proliferation, cell migration, invasion, angiogenesis and metastasis. The FOXM1 as a TF directly or indirectly regulates the expression of several target genes whose dysregulation is associated with almost all hallmarks of cancer. Moreover, FOXM1 expression is associated with chemoresistance to different anti-cancer drugs. Several studies have confirmed that suppression of FOXM1 enhanced the drug sensitivity of various types of cancer cells. Current data suggest that small molecule inhibitors targeting FOXM1 in combination with anticancer drugs may represent a novel therapeutic strategy for chemo-resistant cancers. In this review, we discuss the clinical utility of FOXM1, further, we summarize and discuss small-molecule inhibitors targeting FOXM1 and categorize them according to their mechanisms of targeting FOXM1. Despite great progress, small-molecule inhibitors targeting FOXM1 face many challenges, and we present here all small-molecule FOXM1 inhibitors in different stages of development. We discuss the current challenges and provide insights on the future application of FOXM1 inhibition to the clinic.
The cyclin-dependent kinase inhibitor p21WAF1/CIP1 is a major player in cell cycle control and it is mainly regulated at the transcriptional level. Whereas induction of p21 predominantly leads to ...cell cycle arrest, repression of p21 may have a variety of outcomes depending on the context. In this review, we concentrate on transcriptional repression of p21 by cellular and viral factors, and delve in detail into its possible biological implications and its role in cancer. It seems that the major mode of p21 transcriptional repression by negative regulators is the interference with positive transcription factors without direct binding to the p21 promoter. Specifically, the negative factors may either inhibit binding of positive regulators to the promoter or hinder their transcriptional activity. The ability of p21 to inhibit proliferation may contribute to its tumor suppressor function. Because of this, it is not surprising that a number of oncogenes repress p21 to promote cell growth and tumorigenesis. However, p21 is also an inhibitor of apoptosis and p21 repression may also have an anticancer effect. For example, c-Myc and chemical p21 inhibitors, which repress p21, sensitize tumor cells to apoptosis by anticancer drugs. Further identification of factors that repress p21 is likely to contribute to the better understanding of its role in cancer.
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