TY - JOUR
T1 - Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression
AU - Katsumi, Yoshiki
AU - Iehara, Tomoko
AU - Miyachi, Mitsuru
AU - Yagyu, Shigeki
AU - Tsubai-Shimizu, Satoko
AU - Kikuchi, Ken
AU - Tamura, Shinichi
AU - Kuwahara, Yasumichi
AU - Tsuchiya, Kunihiko
AU - Kuroda, Hiroshi
AU - Sugimoto, Tohru
AU - Houghton, Peter J.
AU - Hosoi, Hajime
N1 - Funding Information:
We thank Ms. Ryoko Murata for secretarial assistance and Mr. Satoshi Nakayama, Mr. Hideki Ishihara (Sysmex Corp.), and Dr. Toshiyuki Sakai (Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine) for analyzing CDK4 activity. This study was supported by Grant-in-Aid (17-13) in Cancer Research, from the Ministry of Health, Labour and Welfare of Japan , a Grant-in-Aid from Children’s Cancer Association of Japan in 2008, and USPHS Grants CA77776 and CA23099 and CA21675 (Cancer Center Support Grant) from the NCI.
PY - 2011/9/16
Y1 - 2011/9/16
N2 - 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%, (IC50 values 0.01 to 0.6μM) 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.
AB - 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%, (IC50 values 0.01 to 0.6μM) 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.
KW - CDK4
KW - INI1
KW - P16
KW - PD 0332991
KW - Rhabdoid tumor
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U2 - 10.1016/j.bbrc.2011.08.047
DO - 10.1016/j.bbrc.2011.08.047
M3 - Article
C2 - 21871868
AN - SCOPUS:80052850363
SN - 0006-291X
VL - 413
SP - 62
EP - 68
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -