Reference - Detail
| RRC ID | 54778 |
|---|---|
| Author | Saeki E, Yasuhira S, Shibazaki M, Tada H, Doita M, Masuda T, Maesawa C. |
| Title | Involvement of C-terminal truncation mutation of kinesin-5 in resistance to kinesin-5 inhibitor. |
| Journal | PLoS One |
| Abstract |
Cultured cells easily develop resistance to kinesin-5 inhibitors (K5Is) often by overexpressing a related motor protein, kinesin-12/KIF15, or by acquiring mutations in the N-terminal motor domain of kinesin-5/KIF11 itself. We aimed to identify novel mechanisms responsible for resistance to S-trityl L-cysteine (STLC), one of the K5Is, using human osteosarcoma cell lines. Among six lines examined, U-2OS and HOS survived chronic STLC treatment and gave rise to resistant cells with IC50s at least 10-fold higher than those of the respective parental lines. Depletion of KIF15 largely eliminated the acquired K5I resistance in both cases, consistent with the proposed notion that KIF15 is indispensable for it. In contrast to the KIF11-independent property of the cells derived from HOS, those derived from U-2OS still required KIF11 for their growth and, intriguingly, expressed a C-terminal truncated variant of KIF11 resulting from a frame shift mutation (S1017fs). All of the isolated clones harbored the same mutation, suggesting its clonal expansion in the cell population due to the growth advantage during chronic STLC treatment. Transgenic expression of KIF11S1017fs in the parental U-2OS cells, as well as in HeLa cells, conferred a moderate but reproducible STLC resistance, probably owing to STLC-resistant localization of the mutant KIF11 on mitotic spindle. Our observations indicate that both KIF15 and the C-terminal-truncated KIF11 contributes to the STLC resistance of the U-2OS derived cells. |
| Volume | 13(12) |
| Pages | e0209296 |
| Published | 2018-12-17 |
| DOI | 10.1371/journal.pone.0209296 |
| PII | PONE-D-18-26132 |
| PMID | 30557316 |
| PMC | PMC6296710 |
| MeSH | Antimitotic Agents / pharmacology* Cell Line, Tumor Cell Survival / drug effects Cysteine / analogs & derivatives* Cysteine / pharmacology Drug Resistance / genetics Drug Resistance / physiology* Dyneins / metabolism Gene Expression Gene Knockdown Techniques HeLa Cells Humans Kinesins / antagonists & inhibitors* Kinesins / genetics Kinesins / metabolism Mutation Nuclear Envelope / drug effects Nuclear Envelope / metabolism Spindle Apparatus / drug effects Spindle Apparatus / metabolism |
| IF | 2.776 |
| Times Cited | 1 |
| Altmetric score |
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 1 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | 293T(RCB2202) |