Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules
Abstract Factor quinolinone inhibitors are promising anti-cancer compounds, initially characterized as specific inhibitors of the oncogenic transcription factor LSF (TFCP2). These compounds exert anti-proliferative activity at least in part by disrupting mitotic spindles. Herein, we report additiona...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-02962-0 |
| _version_ | 1818575599724134400 |
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| author | Patrick Stoiber Pietro Scribani Rossi Niranjana Pokharel Jean-Luc Germany Emily A. York Scott E. Schaus Ulla Hansen |
| author_facet | Patrick Stoiber Pietro Scribani Rossi Niranjana Pokharel Jean-Luc Germany Emily A. York Scott E. Schaus Ulla Hansen |
| author_sort | Patrick Stoiber |
| collection | DOAJ |
| description | Abstract Factor quinolinone inhibitors are promising anti-cancer compounds, initially characterized as specific inhibitors of the oncogenic transcription factor LSF (TFCP2). These compounds exert anti-proliferative activity at least in part by disrupting mitotic spindles. Herein, we report additional interphase consequences of the initial lead compound, FQI1, in two telomerase immortalized cell lines. Within minutes of FQI1 addition, the microtubule network is disrupted, resulting in a substantial, although not complete, depletion of microtubules as evidenced both by microtubule sedimentation assays and microscopy. Surprisingly, this microtubule breakdown is quickly followed by an increase in tubulin acetylation in the remaining microtubules. The sudden breakdown and partial depolymerization of the microtubule network precedes FQI1-induced morphological changes. These involve rapid reduction of cell spreading of interphase fetal hepatocytes and increase in circularity of retinal pigment epithelial cells. Microtubule depolymerization gives rise to FH-B cell compaction, as pretreatment with taxol prevents this morphological change. Finally, FQI1 decreases the rate and range of locomotion of interphase cells, supporting an impact of FQI1-induced microtubule breakdown on cell motility. Taken together, our results show that FQI1 interferes with microtubule-associated functions in interphase, specifically cell morphology and motility. |
| first_indexed | 2024-12-15T00:43:09Z |
| format | Article |
| id | doaj.art-17bb4586a609471589a4fe4bbe029ae8 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-15T00:43:09Z |
| publishDate | 2021-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-17bb4586a609471589a4fe4bbe029ae82022-12-21T22:41:36ZengNature PortfolioScientific Reports2045-23222021-12-0111111510.1038/s41598-021-02962-0Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubulesPatrick Stoiber0Pietro Scribani Rossi1Niranjana Pokharel2Jean-Luc Germany3Emily A. York4Scott E. Schaus5Ulla Hansen6MCBB Graduate Program, Boston UniversityDepartment of Biology, Boston UniversityDepartment of Chemistry, Boston UniversityDepartment of Biology, Boston UniversityDepartment of Chemistry, Boston UniversityDepartment of Chemistry, Boston UniversityMCBB Graduate Program, Boston UniversityAbstract Factor quinolinone inhibitors are promising anti-cancer compounds, initially characterized as specific inhibitors of the oncogenic transcription factor LSF (TFCP2). These compounds exert anti-proliferative activity at least in part by disrupting mitotic spindles. Herein, we report additional interphase consequences of the initial lead compound, FQI1, in two telomerase immortalized cell lines. Within minutes of FQI1 addition, the microtubule network is disrupted, resulting in a substantial, although not complete, depletion of microtubules as evidenced both by microtubule sedimentation assays and microscopy. Surprisingly, this microtubule breakdown is quickly followed by an increase in tubulin acetylation in the remaining microtubules. The sudden breakdown and partial depolymerization of the microtubule network precedes FQI1-induced morphological changes. These involve rapid reduction of cell spreading of interphase fetal hepatocytes and increase in circularity of retinal pigment epithelial cells. Microtubule depolymerization gives rise to FH-B cell compaction, as pretreatment with taxol prevents this morphological change. Finally, FQI1 decreases the rate and range of locomotion of interphase cells, supporting an impact of FQI1-induced microtubule breakdown on cell motility. Taken together, our results show that FQI1 interferes with microtubule-associated functions in interphase, specifically cell morphology and motility.https://doi.org/10.1038/s41598-021-02962-0 |
| spellingShingle | Patrick Stoiber Pietro Scribani Rossi Niranjana Pokharel Jean-Luc Germany Emily A. York Scott E. Schaus Ulla Hansen Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules Scientific Reports |
| title | Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules |
| title_full | Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules |
| title_fullStr | Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules |
| title_full_unstemmed | Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules |
| title_short | Factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules |
| title_sort | factor quinolinone inhibitors alter cell morphology and motility by destabilizing interphase microtubules |
| url | https://doi.org/10.1038/s41598-021-02962-0 |
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