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

Mikhail S Chesnokov,Zarema Arbieva,Carlos J Camacho,Andrei L Gartel,Irum Khan,Rick Oerlemans,Soheila Borhani,Marianna Halasi,Binal N Shah

doi:10.1038/s41419-021-03978-0

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.

Highlights

Forkhead box (FOX) protein M1 (FOXM1) is a transcription factor with pronounced pro-oncogenic functions [1, 2]
Transcriptomic analysis identifies small molecules disrupting FOXM1 pathway The development of pharmaceutical agents inhibiting prooncogenic proteins is a major area in cancer treatment research
FOXM1 level in cells treated simultaneously with STL and CHX showed quick decrease but remained stable for 24 h. These results indicate that FOXM1 is suppressed by STL at the post-translational stage, most likely through increased protein degradation that may be mediated via short-lived proteins

Summary

Introduction

Forkhead box (FOX) protein M1 (FOXM1) is a transcription factor with pronounced pro-oncogenic functions [1, 2]. It is overexpressed in the majority of human cancers and impacts all hallmark tumor aspects, including proliferation, survival, metastasis, inflammation, angiogenesis, and treatment resistance [3,4,5]. It contributes to 5-fluorouracil (5-FU) resistance by promoting ABCC10 transporter expression [8] or causing overexpression of thymidylate synthase, the primary 5-FU target [15]. Inhibition of FOXM1 may prove critical for developing effective therapeutic solutions for cancer chemoresistance problem

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Results

Conclusion