FoxM1 Signaling Pathway Research Articles

In vitro evaluation of Neosetophomone B inducing apoptosis in cutaneous T cell lymphoma by targeting the FOXM1 signaling pathway

BackgroundCutaneous T cell lymphoma (CTCL) is a T cell-derived non-Hodgkin lymphoma primarily affecting the skin, with treatment posing a significant challenge and low survival rates. ObjectiveIn this study, we investigated the anti-cancer potential of Neosetophomone B (NSP-B), a fungal-derived secondary metabolite, on CTCL cell lines H9 and HH. MethodsCell viability was measured using Cell counting Kit-8 (CCK8) assays. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Applied Biosystems' high-resolution Human Transcriptome Array 2.0 was used to examine gene expression. ResultsNSP-B induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases. We observed downregulated expression of BUB1B, Aurora Kinases A and B, cyclin-dependent kinases (CDKs) 4 and 6, and polo-like kinase 1 (PLK1) in NSP-B treated cells, which was further corroborated by Western blot analysis. Notably, higher expression levels of these genes showed reduced overall and progression-free survival in the CTCL patient cohort. FOXM1 and BUB1B expression exhibited a dose-dependent reduction in NSP-B-treated CTCL cells.FOXM1 silencing decreased cell viability and increased apoptosis via BUB1B downregulation. Moreover, NSP-B suppressed FOXM1-regulated genes, such as Aurora Kinases A and B, CDKs 4 and 6, and PLK1. The combined treatment of Bortezomib and NSP-B showed greater efficacy in reducing CTCL cell viability and promoting apoptosis compared to either treatment alone. ConclusionOur findings suggest that targeting the FOXM1 pathway may provide a promising therapeutic strategy for CTCL management, with NSP-B offering significant potential as a novel treatment option.

Dinaciclib inhibits the stemness of two subtypes of human breast cancer cells by targeting the FoxM1 and Hedgehog signaling pathway.

Cyclin‑dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy are the current standard of care used in the first‑line treatment of hormone receptor‑positive/HER2‑negative metastatic breast cancer (BC). Although CDK4/6 inhibitors mainly target the cell cycle, emerging evidence has indicated further potential roles of CDKs other than regulating cell cycle progression. The G1 and G2/M transition regulators, including cyclins D and E, as well as their catalytic partners, CDK2, CDK4 and CDK6, have been reported to play crucial roles in pluripotency maintenance and cell fate decisions of human pluripotent stem cells by controlling transcription factors, signaling pathways and epigenetic regulators. Dinaciclib, a CDK1/2/5/9 inhibitor, is currently being evaluated in clinical trials against various cancer types, including BC. However, the underlying molecular mechanisms of CDK1/2/5/9 inhibitors in regulating BC stemness remain poorly understood. The present study aimed to examine the stemness‑inhibitory effects of dinaciclib in MCF‑7 (luminal) and HCC‑1806 (triple‑negative) BC cells. We found that this drug not only effectively reduced the self‑renewal abilities and other malignant properties, but also dose‑dependently decreased the protein expression levels of three BC stem cell markers, CD44, aldehyde dehydrogenase 1 family member A1 (ALDH1A1) and BMI1 proto‑oncogene, polycomb ring finger (Bmi1), as well as three embryonic stem cell markers, Oct4, Nanog and Sox2. Moreover, the dinaciclib‑induced decrease of Oct4 and Nanog protein expression was able to be restored by co‑treatment with MG‑132, a proteasome inhibitor. Forkhead box M1 (FoxM1), both a stemness‑stimulating transcription factor and a cell cycle regulator, along with the Hedgehog signaling pathway, were identified as the therapeutic targets of dinaciclib. Collectively, the present results demonstrated a novel role of dinaciclib in suppressing BC stemness and indicated its potential use for future cancer treatments.

A novel lncRNA PTTG3P/miR-132/212-3p/FoxM1 feedback loop facilitates tumorigenesis and metastasis of pancreatic cancer

Pseudogene pituitary tumor-transforming 3 (PTTG3P) is emerging as a key player in the development and progression of cancer. However, the biological role and clinical significance of PTTG3P in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, we found that PTTG3P was significantly upregulated in PDAC tissues. Elevated PTTG3P expression correlated with larger tumor size and worse differentiation, and reduced overall survival. Bioinformatics and experimental evidence revealed that PTTG3P promoted malignant phenotypes and FoxM1 signaling pathway in PDAC cells. Mechanistically, PTTG3P functions as a microRNA sponge to positively regulate the expression of FoxM1 through sponging miR-132/212-3p. Moreover, it showed that FoxM1 transcriptionally activated PTTG3P expression, thus forming a feedback loop to promote the aggressiveness of PDAC cells. Taken together, our findings suggest that PTTG3P promotes PDAC progression through PTTG3P/miR-132/212-3p/FoxM1 feedforward circuitry and it may serve as a promising diagnostic marker or target for treatment in PDAC patients.

SPOCK1 overexpression induced by platelet-derived growth factor-BB promotes hepatic stellate cell activation and liver fibrosis through the integrin α5β1/PI3K/Akt signaling pathway

AbstractSparc/osteonectin, cwcv, and kazal-like domain proteoglycan 1 (SPOCK1) is a matricellular protein which regulates cell proliferation, invasion, and survival but the function of SPOCK1 in liver fibrosis is obscure. In this study, we found that SPOCK1 expression increased significantly in fibrotic liver tissues and activated primary rat hepatic stellate cells (R-HSCs). SPOCK1 co-localized with α-smooth muscle actin (α-SMA) in the cytoplasm. Mechanistically, we found platelet-derived growth factor-BB (PDGF-BB) induced SPOCK1 expression by activating the PI3K/Akt/forkhead box M1 (FoxM1) signaling pathway. Intracellular SPOCK1 downregulation decreased the HSC activation, proliferation, and migration induced by PDGF-BB. Furthermore, intracellular SPOCK1 overexpression or recombinant SPOCK1 treatment promoted HSC activation, proliferation, and migration by activating the PI3K/Akt signaling pathway. Co-immunoprecipitation, double immunofluorescence staining indicated that SPOCK1 interacted with integrin α5β1, and neutralization of integrin α5β1 significantly reduced the role of recombinant SPOCK1 in HSCs. In vivo HSC-specific SPOCK1 knockdown following lentivirus administration dramatically ameliorated thioacetamide (TAA)-induced collagen deposition in rat livers. Collectively, our study indicates that SPOCK1 is crucial for hepatic fibrosis and it might be a promising therapeutic target.Matricellular protein SPOCK1 expression positively correlates with liver fibrosis and hepatic stellate cell activation. SPOCK1 is upregulated by PDGF-BB via the PI3K/Akt/FoxM1 signaling pathway and induces pro-fibrogenic responses. Additionally, it promotes stellate cell pro-fibrogenic responses through the integrin α5β1/PI3K/Akt signaling pathway. SPOCK1 is therefore a promising therapeutic target for liver fibrosis.

MMP13 and TIMP1 are functional markers for two different potential modes of action by mesenchymal stem/stromal cells when treating osteoarthritis

Mesenchymal stem cells (MSCs) have been investigated as a potential injectable therapy for the treatment of knee osteoarthritis, with some evidence of success in preliminary human trials. However, optimization and scale-up of this therapeutic approach depends on the identification of functional markers that are linked to their mechanism of action. One possible mechanism is through their chondrogenic differentiation and direct role in neo-cartilage synthesis. Alternatively, they could remain undifferentiated and act through the release of trophic factors that stimulate endogenous repair processes within the joint. Here, we show that extensive in vitro aging of bone marrow-derived human MSCs leads to loss of chondrogenesis but no reduction in trophic repair, thereby separating out the two modes of action. By integrating transcriptomic and proteomic data using Ingenuity Pathway Analysis, we found that reduced chondrogenesis with passage is linked to downregulation of the FOXM1 signaling pathway while maintenance of trophic repair is linked to CXCL12. In an attempt at developing functional markers of MSC potency, we identified loss of mRNA expression for MMP13 as correlating with loss of chondrogenic potential of MSCs and continued secretion of high levels of TIMP1 protein as correlating with the maintenance of trophic repair capacity. Since an allogeneic injectable osteoar therapy would require extensive cell expansion in vitro, we conclude that early passage MMP13+ , TIMP1-secretinghigh MSCs should be used for autologous OA therapies designed to act through engraftment and chondrogenesis, while later passage MMP13- , TIMP1-secretinghigh MSCs could be exploited for allogeneic OA therapies designed to act through trophic repair.

Inhibition of EZH2 and activation of ERRγ synergistically suppresses gastric cancer by inhibiting FOXM1 signaling pathway.

Gastric cancer (GC) is a leading cause of cancer-related mortality worldwide, because of the low efficacy of current therapeutic strategies. Estrogen-related receptor γ (ERRγ) was previously showed as a suppressor of GC. However, the mechanism and effective therapeutic method based on ERRγ is yet to be developed. The expression levels of ERRγ, EZH2, and FOXM1 were detected by immunohistochemistry, qRT-PCR, and western blot. The regulatory mechanisms of ERRγ and FOXM1 were analyzed by ChIP, EMSA, and siRNA. The effects of EZH2 inhibitor (GSK126) or/and ERRγ agonist (DY131) on the tumorigenesis of gastric cancer cell lines were examined by cell proliferation, transwell migration, wound healing, and colony formation assays. Meanwhile, the inhibitory effects of GSK126 or/and DY131 on tumor growth were analyzed by xenograft tumor growth assay. The expression of ERRγ was suppressed in tumor tissues of GC patients and positively correlated with prognosis, as opposed to that of EZH2 and FOXM1. EZH2 transcriptionally suppressed ERRγ via H3K27me3, which subsequently activated the expression of master oncogene FOXM1. The combination of GSK126 and DY131 synergistically activated ERRγ expression, which subsequently inhibited the expression of FOXM1 and its regulated pathways. Synergistic combination of GSK126 and DY131 significantly inhibited the tumorigenesis of GC cell lines and suppressed the growth of GC xenograft. The FOXM1 signaling pathway underlying the ERRγ-mediated gastric cancer suppression was identified. Furthermore, combined treatment with EZH2 inhibitor and ERRγ agonist synergistically suppressed GC progression by inhibiting this signaling pathway, suggesting its high potential in treating GC patients.

Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignancy and is one of the most important cause of cancer related mortalities in the world. However, there is no clinically effective targeted therapeutic drugs for ESCC due to lack of valuable molecular therapeutic targets. In the present study, we investigated the biological function and molecular mechanisms of maternal embryonic leucine zipper kinase (MELK) in ESCC. The expression of MELK mRNA and protein was determined in cell lines and clinical samples of ESCC. MTT, focus formation and soft agar assays were carried out to measure cell proliferation and colony formation. Wound healing and transwell assays were used to assess the capacity of tumor cell migration and invasion. Nude mice models of subcutaneous tumor growth and lung metastasis were performed to examine the function of MELK in tumorigenecity and metastasis of ESCC cells. High expression of MELK was observed in ESCC cell line and human samples, especially in the metastatic tumor tissues. Moreover, overexpression of MELK promoted cell proliferation, colony formation, migration and invasion, and increased the expression and enzyme activity of MMP-2 and MMP-9 in ESCC cells. More importantly, enhanced expression of MELK greatly accelerated tumor growth and lung metastasis of ESCC cells in vivo. In contrast, knockdown of MELK by lentiviral shRNA resulted in an opposite effect both in vitro and in animal models. Mechanistically, MELK facilitated the phosphorylation of FOXM1, leading to activation of its downstream targets (PLK1, Cyclin B1, and Aurora B), and thereby promoted tumorigenesis and metastasis of ESCC cells. In conclusion, MELK enhances tumorigenesis, migration, invasion and metastasis of ESCC cells via activation of FOXM1 signaling pathway, suggesting MELK is a potential therapeutic target for ESCC patients, even those in an advanced stage.

Transcriptional regulation of FoxM1 by HIF‑1α mediates hypoxia‑induced EMT in prostate cancer.

Hypoxia is a tumorigenesis-related microenvironment change which usually occurs in the earliest stage of prostate cancer (PCa) development. Accumulating evidence has demonstrated that hypoxia/hypoxia-inducing factor (HIF) is involved in the induction of epithelial-mesenchymal transition (EMT) and increased metastatic potential in PCa. However, the mechanism by which hypoxia/HIF regulates EMT remains unclear. In the present study, we demonstrated the molecular mechanisms of hypoxia-induced EMT in PCa, focusing on HIF-1α/Forkhead box M1 (FoxM1) signaling pathway. PCa PC3 and DU145 cell lines were used as the model system in vitro. Our data revealed that hypoxia induced EMT in PCa cells. Bioinformatics analysis identified the possible association between HIF-1α and FoxM1. Additionally, FoxM1 was significantly associated with PCa development and Gleason scores of PCa. Exposure to hypoxia resulted in the increased expression of HIF-1α and FoxM1. Genetic knockdown FoxM1 abolished hypoxia-induced EMT in PCa, while exogenous overexpression of FoxM1 facilitated hypoxia-induced EMT. Furthermore, the increase of FoxM1 during hypoxia was due to the transcriptional regulation on the FoxM1 promoter by HIF-1α. We also confirmed the binding site of HIF-1α on the FoxM1 promoter by different lengths promoter sequences. These findings provide new insights into how EMT is regulated in PCa under hypoxic stress. It is worthwhile to investigate in future that inhibition of FoxM1 as a potential target may be an effective therapeutic strategy against PCa.

GLRX inhibition enhances the effects of geftinib in EGFR-TKI-resistant NSCLC cells through FoxM1 signaling pathway

Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer. Gefitinib is one of the most accepted therapies against NSCLC in those carrying EGFR mutations, but it is only effective in approximately 20% of patients with NSCLC. Thus, alternative therapeutic interventions are urgently needed to overcome gefitinib resistance. Glutaredoxin (GLRX) plays a key role in oxidative stress. However, whether GLRX inhibition could enhance gefitinib efficacy in the gefitinib-resistant NSCLC cells is unknown. In this study, we aimed to determine whether combined inhibition of GLRX could enhance growth-inhibitory effects of gefitinib in gefitinib-resistant NSCLC cells. Real-time PCR and western blotting were used to examine the mRNA and protein levels of GLRX in gefitinib-sensitive PC9 and HCC827 and -resistant human lung adenocarcinoma PC9R, HCC827R, and H1975 cells. Cell Counting Kit-8, flow cytometry, JC-1 staining, and reactive oxygen species (ROS) assays were used to evaluate cell proliferation, cell cycle progression, mitochondrial membrane potential, and ROS generation, respectively. Mouse tumor xenografts were used to assess the effect of GLRX in vivo. We found that GLRX was upregulated in gefitinib-resistant PC9R, HCC827R, and H1975 cells. GLRX inhibition enhanced the effects of geftinib in gefitinib-resistant cell proliferation in vitro and in vivo and promoted apoptosis and cell cycle arrest via the EGFR/Forkhead Box M1 (FoxM1) signaling pathway, indicating that combined inhibition of GLRX could enhance growth-inhibitory effects of gefitinib in gefitinib-resistant NSCLC cells. Our results suggest that GLRX inhibition enhances the effects of geftinib in EGFR-TKI-resistant NSCLC cells. Thus, GLRX may represent a therapeutic target for increasing the efficiency of gefitinib treatment.

PCNA-associated factor P15PAF , targeted by FOXM1, predicts poor prognosis in high-grade serous ovarian cancer patients.

Activation of the FOXM1 signaling pathway and the PI3K/AKT/mTOR signaling pathway is associated with poor prognosis in ovarian cancer. In this study, we demonstrated that P15PAF (KIAA0101) was significantly upregulated in high-grade serous ovarian cancer (HGSOC) and that high KIAA0101 expression was associated with poor prognosis. FOXM1 transcriptionally activated KIAA0101 to drive proliferation and metastasis of ovarian cancer cells. KIAA0101 activated the PI3K/AKT/mTOR signaling pathway to inhibit cisplatin-induced apoptosis and autophagy in ovarian cancer cells resulting in cisplatin resistance. Thus, KIAA0101 was closely related to the FOXM1 and PI3K/AKT/mTOR signaling pathways. Collectively, these findings provide insights into the mechanisms of poor prognosis of ovarian cancer and have implications for the development of both predictive and therapeutic biomarkers for the treatment of ovarian cancer.

Sophoridine suppresses cell growth in human medulloblastoma through FoxM1, NF-κB and AP-1.

Sophoridine is an alkaloid extracted from Sophora alopecuroides that has extensive pharmacological actions. In the present study, the effect of sophoridine on cell growth of human medulloblastoma and its mechanism were investigated. Human medulloblastoma D283-Med cells were incubated with 0, 0.5, 1 or 2 mg/ml sophoridine for 24, 48 or 72 h. Cell proliferation and cytotoxicity were analyzed using MTT and lactate dehydrogenase assays, respectively. Next, analyses of cell apoptosis and caspase-3/8 activity were performed using flow cytometry or spectrophotometry, respectively. Lastly, the change in FoxM1, TrkB, BDNF, NF-κB and AP-1 expression was investigated using western blot analysis. In the present study, treatment with sophoridine significantly suppressed cell growth and induced apoptosis in human medulloblastoma cells. In addition, sophoridine significantly increased cytotoxicity and caspase-3/8 activity in human medulloblastoma. Finally, it was found that sophoridine suppresses the protein expression of FoxM1, TrkB, BDNF NF-κB and AP-1 in human medulloblastoma cells. The present study suggests that sophoridine suppresses cell growth of human medulloblastoma through the inhibition of the FoxM1, NF-κB and AP-1 signaling pathway.

A novel integrative risk index of papillary thyroid cancer progression combining genomic alterations and clinical factors.

Although the majority of papillary thyroid cancer (PTC) is indolent, a subset of PTC behaves aggressively despite the best available treatment. A major clinical challenge is to reliably distinguish early on between those patients who need aggressive treatment from those who do not. Using a large cohort of PTC samples obtained from The Cancer Genome Atlas (TCGA), we analyzed the association between disease progression and multiple forms of genomic data, such as transcriptome, somatic mutations, and somatic copy number alterations, and found that genes related to FOXM1 signaling pathway were significantly associated with PTC progression. Integrative genomic modeling was performed, controlling for demographic and clinical characteristics, which included patient age, gender, TNM stages, histological subtypes, and history of other malignancy, using a leave-one-out elastic net model and 10-fold cross validation. For each subject, the model from the remaining subjects was used to determine the risk index, defined as a linear combination of the clinical and genomic variables from the elastic net model, and the stability of the risk index distribution was assessed through 2,000 bootstrap resampling. We developed a novel approach to combine genomic alterations and patient-related clinical factors that delineates the subset of patients who have more aggressive disease from those whose tumors are indolent and likely will require less aggressive treatment and surveillance (p = 4.62 × 10–10, log-rank test). Our results suggest that risk index modeling that combines genomic alterations with current staging systems provides an opportunity for more effective anticipation of disease prognosis and therefore enhanced precision management of PTC.

Concordant dysregulation of miR-5p and miR-3p arms of the same precursor microRNA may be a mechanism in inducing cell proliferation and tumorigenesis: a lung cancer study.

A precursor microRNA (miRNA) has two arms: miR-5p and miR-3p (miR-5p/-3p). Depending on the tissue or cell types, both arms can become functional. However, little is known about their coregulatory mechanisms during the tumorigenic process. Here, by using the large-scale miRNA expression profiles of five cancer types, we revealed that several of miR-5p/-3p arms were concordantly dysregulated in each cancer. To explore possible coregulatory mechanisms of concordantly dysregulated miR-5p/-3p pairs, we developed a robust computational framework and applied it to lung cancer data. The framework deciphers miR-5p/-3p coregulated protein interaction networks critical to lung cancer development. As a novel part in the method, we uniquely applied the second-order partial correlation to minimize false-positive regulations. Using 279 matched miRNA and mRNA expression profiles extracted from tumor and normal lung tissue samples, we identified 17 aberrantly expressed miR-5p/-3p pairs that potentially modulate the gene expression of 35 protein complexes. Functional analyses revealed that these complexes are associated with cancer-related biological processes, suggesting the oncogenic potential of the reported miR-5p/-3p pairs. Specifically, we revealed that the reduced expression of miR-145-5p/-3p pair potentially contributes to elevated expression of genes in the “FOXM1 transcription factor network” pathway, which may consequently lead to uncontrolled cell proliferation. Subsequently, the regulation of miR-145-5p/-3p in the FOXM1signaling pathway was validated by a cohort of 104 matched miRNA and protein (reverse-phase protein array) expression profiles in lung cancer. In summary, our computational framework provides a novel tool to study miR-5p/-3p coregulatory mechanisms in cancer and other diseases.

Editorial (Thematic Issue: Advances with microRNAs in Tumorigenesis and Cancer Therapy)

Recent studies have highlighted the pivotal role of microRNAs (miRNAs) in tumorigenesis. A growing body of data implicates that miRNAs are critically involved in regulation of cell growth, cell cycle, apoptosis, migration, invasion, angiogenesis, metastasis, epithelial to mesenchymal transition (EMT), cancer stem cell renewal, and drug resistance. Therefore, our special issue reviewed the important role of miRNAs in the development and progression of human cancers. It has been accepted that miRNAs play an essential role in human malignancies. Dr. Markel et al. reviewed the diverse roles of miRNAs in regulation of cell cycle, proliferation, migration, invasion and drug resistance in melanoma cell biology [1]. Moreover, Dr. Zhou et al. discussed the oncogenic miRNAs in the genesis of leukemia and lymphoma, suggesting that miRNAs could be novel targets for anti-leukemia and anti-lymphoma drug discovery [2]. Dr. Sarkar et al. summarized the function of miRNAs in breast cancer tumorigenesis and metastasis, and provided the current knowledge of miRNAs as molecular targets for diagnosis, prognosis and therapy in breast cancer [3]. Emerging evidence has suggested that miRNAs exert its biological functions through governing key signaling pathways. To support this concept, Dr. Azmi et al. summarized that a number of miRNAs control Kras-PAK4 (p21 activated kinase 4) axis in cancer [4]. Dr. Xie et al. discussed that miRNAs are key players in pancreatic cancer initiation and progression through regulating FOXM1 signaling pathway [5]. Furthermore, Dr. Batra and colleagues summarized miRNAs as biomarkers for prognosis and diagnosis of gastrointestinal cancers and gastrointestinal tract associated organs including esophagus, gastric, liver, pancreas, and colon [6]. Intriguingly, Dr. Lu et al. discussed the developments on the regulatory role of miRNAs in circulating tumor cells and thrombosis, suggesting that targeting miRNAs could be useful for the treatment and prevention of metastasis and thrombosis in cancer [7]. It is noteworthy that miRNAs have been demonstrated to be involved in EMT progress. Dr. Yang et al. described that multiple miRNAs regulated EMT-inducing transcription factors such as Notch and TGF-β, leading to regulation of EMT in cancer [8]. Since EMT and miRNAs are associated with cancer stem cells (CSCs), Dr. Watabe et al. discussed how miRNAs regulate CSCs through different self-renewal pathways in various types of human cancers [9]. More importantly, Dr. Croce et al. discussed approaches towards therapeutic miRNA-based intervention including viral or non-viral approaches of miRNA replacement therapy [10]. Remarkably, Dr. Fan et al. summarized the implication of miRNAs in clinical use and challenge for miRNA based therapy such as miRNA delivery [11]. Notably, Dr. Wang et al. demonstrated that natural agent genistein down-regulated oncomiR-27a in pancreatic cancer cells, indicating that genistein could be a miR-27a inhibitor [12]. Dr. Chen et al. observed that arsenic trioxide exerts its anti-tumor activity partly through regulation of miR-125b in glioma cells [13]. Taken together, targeting miRNAs could be a novel strategy for treatment of cancer. Lastly, as the editor, I would like to thank the authors for their contributions. I also would like to appreciate the referees for their timely reviews. We hope that this special issue will help identify novel therapeutic targets to treat human cancers.

Abstract 1008: Prevalence of FoxM1 expression in Middle Eastern epithelial ovarian carcinoma patients and its potential role as a therapeutic target

Abstract FoxM1 is a member of Forkhead transcription factors and its expression has been found to be altered in a variety of cancers. Several studies have indicated the importance of FoxM1 in cell proliferation, as it is a key cell-cycle regulator of both the transition from G1 to S phase and the progression to mitosis. In this study, we investigated the functional consequences of FoxM1 signaling pathway in a large cohort of epithelial ovarian cancer (EOC) tumor (patient) samples, panel of cell lines, and in nude mouse model. Using immunohistochemistry, FoxM1 was detected in 47.4% (64/135) of the ovarian tumor samples. EOC with FOX-M1 expression showed a significantly better disease free survival(p=0.0148) of 21.9 months as compared to the EOC with low FOX-M1 expression(14.4 months). Overexpression of FoxM1 was also significantly associated with activated p-AKT(p=0.0072), SKP2(p=0.0121), p-Rb(p=0.0357), UBE2C(p=0.0106), FAS-N(p=0.0179), PIK3CA p110αIHC(p=0.0362), XIAP(p=0.0033) and tumor proliferative marker Ki167 (p<0.0001). Treatment of a panel of EOC cell lines with thiostrepton, an inhibitor of FoxM1, inhibited cell proliferation and induced apoptosis. Thiostrepton treatment caused apoptosis by involving the mitochondrial pathway, through activation of caspases and down regulation of XIAP and survivin. FoxM1 inhibition in EOC cells by thiostrepton resulted in the down regulation of Skp2 and accumulation of p21, possibly causing G2/M arrest. Furthermore, FoxM1 inhibition also down regulated cell migration and cell invasion in EOC cells by inducing decreased secretion of VEGF and MMP2. In addition, pharmacological inhibition of FoxM1 or its gene silencing with siRNA causes downregulation of FoxM1, AKT and its associated downstream signaling molecules. Altogether, these results suggest that FoxM1 and its role in the deregulated survival pathway make this a potential target for therapeutic intervention of EOC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1008. doi:10.1158/1538-7445.AM2011-1008