title: Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance.
abstract: FOXM1 has been implicated in taxane resistance, but the molecular mechanism involved remains elusive. In here, we show that FOXM1 depletion can sensitize breast cancer cells and mouse embryonic fibroblasts into entering paclitaxel-induced senescence, with the loss of clonogenic ability, and the induction of senescence-associated β-galactosidase activity and flat cell morphology. We also demonstrate that FOXM1 regulates the expression of the microtubulin-associated kinesin KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Similar to FOXM1, KIF20A expression is downregulated by paclitaxel in the sensitive MCF-7 breast cancer cells and deregulated in the paclitaxel-resistant MCF-7Tax(R) cells. KIF20A depletion also renders MCF-7 and MCF-7Tax(R) cells more sensitive to paclitaxel-induced cellular senescence. Crucially, resembling paclitaxel treatment, silencing of FOXM1 and KIF20A similarly promotes abnormal mitotic spindle morphology and chromosome alignment, which have been shown to induce mitotic catastrophe-dependent senescence. The physiological relevance of the regulation of KIF20A by FOXM1 is further highlighted by the strong and significant correlations between FOXM1 and KIF20A expression in breast cancer patient samples. Statistical analysis reveals that both FOXM1 and KIF20A protein and mRNA expression significantly associates with poor survival, consistent with a role of FOXM1 and KIF20A in paclitaxel action and resistance. Collectively, our findings suggest that paclitaxel targets the FOXM1-KIF20A axis to drive abnormal mitotic spindle formation and mitotic catastrophe and that deregulated FOXM1 and KIF20A expression may confer paclitaxel resistance. These findings provide insights into the underlying mechanisms of paclitaxel resistance and have implications for the development of predictive biomarkers and novel chemotherapeutic strategies for paclitaxel resistance.
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Khongkow
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Gomes
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: C
authors.initials: C
authors.lastname: Gong
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: E P S
authors.initials: EP
authors.lastname: Man
authors.affiliation: Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: J W-H
authors.initials: JW
authors.lastname: Tsang
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.|Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: F
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Monteiro
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Coombes
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Medema
authors.affiliation: Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: U S
authors.initials: US
authors.lastname: Khoo
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
authors.forename: E W-F
authors.initials: EW
authors.lastname: Lam
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D008941:Spindle Apparatus / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C410089:KIF20A protein, human; D016547:Kinesins; D017239:Paclitaxel