Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells
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 STL42794...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-03978-0 |
| _version_ | 1818624255412142080 |
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| author | Mikhail S. Chesnokov Marianna Halasi Soheila Borhani Zarema Arbieva Binal N. Shah Rick Oerlemans Irum Khan Carlos J. Camacho Andrei L. Gartel |
| author_facet | Mikhail S. Chesnokov Marianna Halasi Soheila Borhani Zarema Arbieva Binal N. Shah Rick Oerlemans Irum Khan Carlos J. Camacho Andrei L. Gartel |
| author_sort | Mikhail S. Chesnokov |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T18:54:03Z |
| format | Article |
| id | doaj.art-3babdd7ba88c4a3193ab9166ae0d1cb3 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-16T18:54:03Z |
| publishDate | 2021-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-3babdd7ba88c4a3193ab9166ae0d1cb32022-12-21T22:20:36ZengNature Publishing GroupCell Death and Disease2041-48892021-07-0112711310.1038/s41419-021-03978-0Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cellsMikhail S. Chesnokov0Marianna Halasi1Soheila Borhani2Zarema Arbieva3Binal N. Shah4Rick Oerlemans5Irum Khan6Carlos J. Camacho7Andrei L. Gartel8University of Illinois at Chicago, Department of MedicineUniversity of Illinois at Chicago, Department of MedicineUniversity of Illinois at Chicago, Department of MedicineUniversity of Illinois at Chicago, Genome Research CoreUniversity of Illinois at Chicago, Department of MedicineUniversity of Pittsburgh, College of MedicineUniversity of Illinois at Chicago, Department of MedicineUniversity of Pittsburgh, College of MedicineUniversity of Illinois at Chicago, Department of MedicineAbstract 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.https://doi.org/10.1038/s41419-021-03978-0 |
| spellingShingle | Mikhail S. Chesnokov Marianna Halasi Soheila Borhani Zarema Arbieva Binal N. Shah Rick Oerlemans Irum Khan Carlos J. Camacho Andrei L. Gartel Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells Cell Death and Disease |
| title | Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells |
| title_full | Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells |
| title_fullStr | Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells |
| title_full_unstemmed | Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells |
| title_short | Novel FOXM1 inhibitor identified via gene network analysis induces autophagic FOXM1 degradation to overcome chemoresistance of human cancer cells |
| title_sort | novel foxm1 inhibitor identified via gene network analysis induces autophagic foxm1 degradation to overcome chemoresistance of human cancer cells |
| url | https://doi.org/10.1038/s41419-021-03978-0 |
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