FoxM1, a critical regulator of oxidative stress during oncogenesis

Abstract

The transcription factor FoxM1 is over-expressed in most human malignancies. Although it is evident that FoxM1 has critical functions in tumour development and progression, the mechanisms by which FoxM1 participates in those processes are not understood. Here, we describe an essential role of FoxM1 in the regulation of oxidative stress that contributes to malignant transformation and tumour cell survival. We identify a negative feedback loop involving FoxM1 that regulates reactive oxygen species (ROS) in proliferating cells. We show that induction of FoxM1 by oncogenic Ras requires ROS. Elevated FoxM1, in turn, downregulates ROS levels by stimulating expression of ROS scavenger genes, such as MnSOD, catalase and PRDX3. FoxM1 depletion sensitizes cells to oxidative stress and increases oncogene-induced premature senescence. Moreover, tumour cells expressing activated AKT1 are 'addicted' to FoxM1, as they require continuous presence of FoxM1 for survival. Together, our results identify FoxM1 as a key regulator of ROS in dividing cells, and provide insights into the mechanism how tumour cells use FoxM1 to control oxidative stress to escape premature senescence and apoptosis.

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

“…FoxM1 has been shown to activate the oncogenic pathways that are important in carcinogenesis such as mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), phosphatdyl inositol 3-kinase (PI3k)/Akt), nuclear factor kappa-B and sonic hedgehog (SHH) [33][34][35][36][37]. Moreover, FoxM1 has been shown to decrease the gene expression levels of the tumor suppressor genes and also the genes involved in cellular senescence like p53 and p21 cip1 [20,38].…”

Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras–MKK3–p38 to regulate in vitro cellular invasion

“…Moreover, this transcription factor appears to play a major role in early tumorigenesis of head and neck squamous cell cancers (Gemenetzidis et al, 2009) and seems not to induce apoptosis (Kalinina et al, 2003;Gusarova et al, 2007;Park et al, 2009). It displays a proliferation-specific expression pattern.…”

“…This gene encodes a forkhead/wingedhelix transcription factor that regulates malignant growth and invasion (Wierstra and Alves, 2007). However, it does not induce apoptosis (Kalinina et al, 2003;Gusarova et al, 2007;Park et al, 2009) (Figure 5e) that was more pronounced in ras-transformed cells and could be abolished by incubating ras-and MKK3 act -transformed cells with the p38 inhibitor SB203580 (Figure 5f). Thus, FOXM1 should be considered downstream of the Ha-Ras-MKK3-p38 cascade.…”

“…In this study we have been able to observe FOXM1 to act downstream from RAS-MKK3-p38 and confer invasion and anchorageindependent growth signals. Recently published data demonstrate furthermore, that upregulation of FOXM1 prevents apoptosis and senescence (Park et al, 2009) and may even be downregulated upon induction of dormancy through p38 (Adam et al, 2009). Thus, FOXM1 may serve as a therapeutic target to eliminate those effects of the p38 pathway that support the malignant phenotype, without affecting possible induc- Figure 6 siRNA-mediated knockdown of FoxM1leads to downregulation of p38-dependent invasion, which can be restored by overexpression of FoxM1.…”

MnSOD Promotes Tumor Invasion via Upregulation of FoxM1–MMP2 Axis and Related with Poor Survival and Relapse in Lung Adenocarcinomas

“…Several studies have implicated FoxM1 in tumorigenesis, as it is overexpressed in various human cancers including lung cancer (24)(25)(26)(27)(28). Wang and colleagues showed that proliferation of lung tumor cells was diminished in Mx-Cre FoxM1 À/À mouse mutants and that these mice had a significant reduction in the number and size of lung adenomas (28).…”