title: Effect of AKT3 expression on MYC- and caspase-8-dependent apoptosis caused by polo-like kinase inhibitors in HCT 116 cells.
abstract: Polo-like kinase (PLK) is a cell-cycle regulator that is overexpressed in several cancer cell types. Polo-like kinase is considered a novel target for cancer therapies, and several PLK inhibitors (PLKis), including BI 2536, BI 6727, and GSK461364, have been developed. In this study, we established five BI 2536-resistant cell lines from human colorectal cancer HCT 116 cells, to explore the resistance mechanism and identify predictable biomarkers of PLKis. We showed that PLKi-induced caspase-8 activation was attenuated in the BI 2536-resistant cell lines. We also showed that the expression of P-glycoprotein (P-GP) and AKT3 was upregulated, whereas that of MYC was downregulated in some BI 2536-resistant cell lines. Expression of P-GP conferred resistance to PLKis, and PLKi-induced apoptosis was dependent on MYC and caspase-8 in HCT 116 cells. We also showed for the first time that AKT3 suppressed BI 6727-induced caspase-8 activation and conferred resistance to PLKis. Collectively, these results indicate that MYC, caspase-8, P-GP, and AKT3 play critical roles in PLKi-induced apoptosis. Therefore, they are candidate biomarkers of the pharmacological efficacy of PLKis.
authors.affiliation: Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Nonomiya
authors.affiliation: Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kasagaki
authors.affiliation: Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Katayama
authors.affiliation: Division of Chemotherapy, Faculty of Pharmacy, Keio University, Tokyo, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D053181:Caspase 8 / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D000097869:Polo-Like Kinase 1
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053181:Caspase 8; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D011804:Quinolines; D000097869:Polo-Like Kinase 1; C087719:dofequidar; C491754:AKT3 protein, human
keywords: AKT3; apoptosis; drug resistance; inhibitor; kinase