title: Mitotic slippage and expression of survivin are linked to differential sensitivity of human cancer cell-lines to the Kinesin-5 inhibitor monastrol.
abstract: The mitotic Kinesin-5 motor proteins crosslink and slide apart antiparallel spindle microtubules, thus performing essential functions in mitotic spindle dynamics. Specific inhibition of their function by monastrol-like small molecules has been examined in clinical trials as anticancer treatment, with only partial success. Thus, strategies that improve the efficiency of monastrol-like anticancer drugs are required. In the current study, we examined the link between sensitivity to monastrol and occurrence of mitotic slippage in several human cell-lines. We found that the rank of sensitivity to monastrol, from most sensitive to least sensitive, is: AGS > HepG2 > Lovo > Du145 ≥ HT29. We show correlation between the sensitivity of a particular cell-line to monastrol and the tendency of the same cell-line to undergo mitotic slippage. We also found that in the monastrol resistant HT29 cells, prolonged monastrol treatments increase mRNA and protein levels of the chromosomal passenger protein survivin. In contrast, survivin levels are not increased by this treatment in the monastrol-sensitive AGS cells. We further show that over-expression of survivin in the monastrol-sensitive AGS cells reduces mitotic slippage and increases resistance to monastrol. Finally, we show that during short exposure to monastrol, Si RNA silencing of survivin expression reduces cell viability in both AGS and HT29 cells. Our data suggest that the efficiency of anti-cancer treatment with specific kinesin-5 inhibitors may be improved by modulation of expression levels of survivin.
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Asraf
authors.affiliation: Department of Chemistry, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Avunie-Masala
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
authors.affiliation: Department of Chemistry, Faculty of Natural Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Larisa
authors.initials: L
authors.lastname: Gheber
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D008941:Spindle Apparatus / Q000187:drug effects; D000077022:Survivin; D013871:Thiones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000077022:Survivin; D013871:Thiones; C400223:monastrol; D016547:Kinesins