A novel FOXM1-BCL2A1 axis determines unfavourable response to venetoclax in AML.

Forkhead box M1 (FOXM1), a Forkhead family transcription factor, is often overexpressed in a variety of human cancers, including AML and strongly associated with therapy resistance and unfavourable outcomes. In AML with NPM1 mutations NPM1/FOXM1 complex sequesters FOXM1 in the cytoplasm and confers favourable treatment outcomes for AML patients, because of FOXM1 inactivation. Inhibition of FOXM1 in AML cell lines and animal models of AML sensitizes AML cells to the Bcl2-inhibitor, venetoclax.

Novel FOXM1 inhibitor STL001 sensitizes human cancers to a broad-spectrum of cancer therapies.

Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy resistance and less good patient survival. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug resistance, making the therapy less effective. NPM1 mutation through the inactivation of FOXM1 via FOXM1 relocalization to the cytoplasm confers more favorable treatment outcomes for AML patients, confirming FOXM1 as a crucial target to overcome drug resistance.

Regulation of HOX gene expression in AML.

As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1) AML comprising a third of all AML patients.

Small-molecule inhibitors targeting FOXM1: Current challenges and future perspectives in cancer treatments.

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.

FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML.

Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear.

Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells.

FOXM1 transcription factor is an oncogene and a master regulator of chemoresistance in multiple cancers. Pharmacological inhibition of FOXM1 is a promising approach but has proven to be challenging. We performed a network-centric transcriptomic analysis to identify a novel compound STL427944 that selectively suppresses FOXM1 by inducing the relocalization of nuclear FOXM1 protein to the cytoplasm and promoting its subsequent degradation by autophagosomes.

Therapeutic Vulnerabilities of Transcription Factors in AML.

Acute myeloid leukemia (AML) is characterized by impaired myeloid lineage differentiation, uncontrolled proliferation, and inhibition of proapoptotic pathways. In spite of a relatively homogeneous clinical disease presentation, risk of long-term survival in AML varies from 20% to 80% depending on molecular disease characteristics. In recognition of the molecular heterogeneity of AML, the European Leukemia Net (ELN) and WHO classification systems now incorporate cytogenetics and increasing numbers of gene mutations into AML prognostication.

FOXM1: a potential therapeutic target in human solid cancers.

: 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.: 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.

FOXM1 contributes to treatment failure in acute myeloid leukemia.

Acute myeloid leukemia (AML) patients with NPM1 mutations demonstrate a superior response to standard chemotherapy treatment. Our previous work has shown that these favorable outcomes are linked to the cytoplasmic relocalization and inactivation of FOXM1 driven by mutated NPM1. Here, we went on to confirm the important role of FOXM1 in increased chemoresistance in AML.

Honokiol is a FOXM1 antagonist.

Honokiol is a natural product and an emerging drug for a wide variety of malignancies, including hematopoietic malignancies, sarcomas, and common epithelial tumors. The broad range of activity of honokiol against numerous malignancies with diverse genetic backgrounds suggests that honokiol is inhibiting an activity that is common to multiple malignancies. Oncogenic transcription factor FOXM1 is one of the most overexpressed oncoproteins in human cancer.

FOXM1 in Cancer: Interactions and Vulnerabilities.

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.

A Novel Function of Molecular Chaperone HSP70: SUPPRESSION OF ONCOGENIC FOXM1 AFTER PROTEOTOXIC STRESS.

The oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers, and it is a potential target for anticancer therapy. We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Here we found that HSP90 inhibitor PF-4942847 and heat shock also suppress FOXM1.

Mutual Regulation of FOXM1, NPM and ARF Proteins.

ARF, NPM and FOXM1 proteins interact with each other in mammalian cells. We showed previously that proteasome inhibitors suppress not only FOXM1 expression, but also the expression of ARF and NPM proteins. Using RNA interference we found that the depletion of each of these proteins by RNAi in human cancer HeLa cells leads to down-regulation of the two other partners, suggesting that these proteins stabilize each other in human cancer cells.

Proteasome inhibitors suppress the protein expression of mutant p53.

Tumor suppressor p53 is one of the most frequently mutated genes in cancer, with almost 50% of all types of cancer expressing a mutant form of p53. p53 transactivates the expression of its primary negative regulator, HDM2. HDM2 is a ubiquitin ligase, which initiates the proteasomal degradation of p53 following ubiquitination.

Suppression of the Oncogenic Transcription Factor FOXM1 by Proteasome Inhibitors.

The oncogenic transcription factor FOXM1 is one of the key regulators of tumorigenesis. We found that FOXM1 upregulates its own transcription and its protein stability depends on its interaction with the chaperone nucleophosmin. We also determined that FOXM1 is negatively regulated by the tumor suppressor p53.

ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

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.

Combination of oxidative stress and FOXM1 inhibitors induces apoptosis in cancer cells and inhibits xenograft tumor growth.

Tumor cells accumulate high level of reactive oxygen species (ROS) because they are metabolically more active than normal cells. Elevated ROS levels increase tumorigenecity but also render cancer cells more vulnerable to oxidative stress than normal 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.

FOX(M1) news--it is cancer.

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.

Paradoxical inhibition of cellular protein expression by proteasome inhibitors.

Abstract Proteasome inhibitors are used as anticancer drugs, however, the precise mechanisms of their selective activity against cancer cells are not understood well. While proteasome inhibitors stabilize the majority of cellular proteins through inhibition of proteasome activity, they also paradoxically downregulate several other proteins. We recently discovered that proteasome inhibitors suppress mRNA and protein expression of FOXM1, NPM, and ARF proteins that are involved in cancer.

Targeting FOXM1 in cancer.

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.

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding.