title: Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression.
abstract: Malignant rhabdoid tumor (MRT) is a rare and highly aggressive neoplasm of young children. MRT is characterized by inactivation of integrase interactor 1 (INI1). Cyclin-dependent kinase 4 (CDK4), which acts downstream of INI1, is required for the proliferation of MRT cells. Here we investigated the effects of PD 0332991 (PD), a potent inhibitor of CDK4, against five human MRT cell lines (MP-MRT-AN, KP-MRT-RY, G401, KP-MRT-NS, KP-MRT-YM). In all of the cell lines except KP-MRT-YM, PD inhibited cell proliferation >50%, (IC(50) values 0.01 to 0.6 μM) by WST-8 assay, and induced G1-phase cell cycle arrest, as shown by flow cytometry and BrdU incorporation assay. The sensitivity of the MRT cell lines to PD was inversely correlated with p16 expression (r=0.951). KP-MRT-YM cells overexpress p16 and were resistant to the growth inhibitory effect of PD. Small interfering RNA against p16 significantly increased the sensitivity of KP-MRT-YM cells to PD (p<0.05). These results suggest that p16 expression in MRT could be used to predict its sensitivity to PD. PD may be an attractive agent for patients with MRT whose tumors express low levels of p16.
authors.affiliation: Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kawaramachi-hirokoji, Kyoto 602-8566, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Katsumi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Iehara
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Miyachi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Yagyu
authors.forename: Satoko
authors.initials: S
authors.lastname: Tsubai-Shimizu
authors.forename: Ken
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Tamura
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Kuwahara
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kuroda
authors.forename: Tohru
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Hajime
authors.initials: H
authors.lastname: Hosoi
mesh_terms: D045744:Cell Line, Tumor; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm; D006367:HeLa Cells; D006801:Humans; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D018335:Rhabdoid Tumor / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D018844:Cyclin-Dependent Kinases; C500026:palbociclib