title: Inhibition of polo like kinase 1 in sarcomas induces apoptosis that is dependent on Mcl-1 suppression.
abstract: Sarcomas are rare cancers and the current treatments in inoperable or metastatic disease have not been shown to prolong survival. In order to develop novel targeted therapies, we tested the efficacy of polo-like kinase 1 (PLK-1) inhibitor (TAK-960) in sarcoma. All the sarcoma cell lines were sensitive to TAK-960 with IC50s in the low nanomolar range. We chose MPNST, CHP100 and LS141 for our studies and of which MPNST cells exclusively underwent polyploidy after a delay in mitosis for about 18 hours; CHP100 cells, after a 24h mitotic delay, died of apoptosis; LS141, after a delay in mitosis stayed at 4N with mild apoptosis. Apoptosis induced by TAK-960 in CHP100 was associated with down-regulation of Mcl-1 and the effect was recapitulated by down-regulating PLK1 by siRNA, confirming that the effect of TAK-960 on Mcl-1 expression is target specific. With suppression of Mcl-1 by siRNA, TAK-960 induced apoptosis in MPNST cells as well. These effects were confirmed in vivo, such that TAK-960 more effectively inhibited CHP100 than MPNST xenografts. In the setting of PLK-1 inhibition, Mcl-1 down regulation is shown to be an important determinant of apoptosis. Collectively, the net effect of this is to drive cells to apoptosis, resulting in a greater anti-tumor effect in vivo. Therefore, targeting PLK-1 should have a greater impact in treating sarcomas provided there is concomitant suppression of Mcl-1. These results further indicate that Mcl-1 could be an important biomarker to predict sensitivity to the induction of apoptosis by PLK-1 targeted therapy in sarcoma.
authors.affiliation: a Jennifer Goodman Linn Laboratory of New Drug Development; Department of Medicine; Memorial Sloan-Kettering Cancer Center ; New York , NY USA.
authors.forename: Jayasree S
authors.initials: JS
authors.lastname: Nair
authors.affiliation: a Jennifer Goodman Linn Laboratory of New Drug Development; Department of Medicine; Memorial Sloan-Kettering Cancer Center ; New York , NY USA.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D010129:4-Aminobenzoic Acid / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012509:Sarcoma / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D010129:4-Aminobenzoic Acid; D001381:Azepines; D018797:Cell Cycle Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C573314:4-((9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido(4,5-b)(1,4)diazepin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse
keywords: Mcl-1; PLK1; apoptosis; polyploidy; sarcoma