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

AI Article Synopsis

  • * Researchers identified a new compound, STL427944, that inhibits FOXM1 by moving it from the nucleus to the cytoplasm for degradation, enhancing cancer cell sensitivity to traditional chemotherapy drugs.
  • * Transcriptomic analysis showed that STL427944 effectively suppresses FOXM1-related gene signatures without affecting other major pathways, highlighting its selectivity and potential to improve cancer treatment outcomes.

Article Abstract

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. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic treatments (platinum-based agents, 5-fluorouracil, and taxanes). RNA-seq analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 toward the FOXM1 pathway. Collectively, the novel autophagy-dependent mode of FOXM1 suppression by STL427944 validates a unique pathway to overcome tumor chemoresistance and improve the efficacy of treatment with conventional cancer drugs.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280155PMC
http://dx.doi.org/10.1038/s41419-021-03978-0DOI Listing

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