TY - JOUR
T1 - Downregulation of XIAP and induction of apoptosis by the synthetic cyclin-dependent kinase inhibitor GW8510 in non-small cell lung cancer cells
AU - Dong, Fengqin
AU - Guo, Wei
AU - Zhang, Lidong
AU - Wu, Shuhong
AU - Teraishi, Fuminori
AU - Davis, John J.
AU - Fang, Bingliang
N1 - Funding Information:
We thank Don Norwood for editorial review of the manuscript. National Cancer Institute grants RO1 CA 092487-01A1 and RO1 CA 098582-01A1 (both to B. Fang), National Cancer Institute Lung Specialized Program of Research Excellence, and National Institutes of Health Core Grant CA-16672.
PY - 2006/2
Y1 - 2006/2
N2 - Small-molecule inhibitors of cyclin-dependent kinases (CDKs) are known to induce cell cycle arrest and apoptosis in certain cancer cells. In order to evaluate the antitumor activity of one such inhibitor, GW8510, against human lung cancers, we analyzed the effects of GW8510 on six nonsmall cell lung cancer (NSCLC) cell lines (A549, H1299, H460, H226, H358 and H322) and normal human fibroblast (NHFB). We treated the cells with GW8510 at concentrations of 0-10 μM, and found that it suppressed cell growth in vitro in all the lung cancer cells but not in NHFB. Subsequent study showed that GW8510 induced apoptosis and cell cycle arrest in the A549, H1299 and H460 cells in a time-and dose-dependent manner. Western blot analysis showed that GW8510 downregulated the expression of X-linked inhibitor of apoptosis (XIAP) but had no detectable effect on the expression of Bax, Bak, or Bcl2. GW8510 also downregulated XIAP mRNA level, suggesting that downregulation of XIAP expression occurs at the transcriptional level. Moreover, ectopic XIAP expression diminished growth inhibition and apoptosis induction by GW8510. Importantly, GW8510 was not capable of inducing apoptosis of NHFB cells. These results suggest that GW8510 might provide a treatment strategy for human NSCLC and XIAP is an important target for GW8510-induced apoptosis of NSCLC cells that occurs through inhibition of XIAP mRNA transcription.
AB - Small-molecule inhibitors of cyclin-dependent kinases (CDKs) are known to induce cell cycle arrest and apoptosis in certain cancer cells. In order to evaluate the antitumor activity of one such inhibitor, GW8510, against human lung cancers, we analyzed the effects of GW8510 on six nonsmall cell lung cancer (NSCLC) cell lines (A549, H1299, H460, H226, H358 and H322) and normal human fibroblast (NHFB). We treated the cells with GW8510 at concentrations of 0-10 μM, and found that it suppressed cell growth in vitro in all the lung cancer cells but not in NHFB. Subsequent study showed that GW8510 induced apoptosis and cell cycle arrest in the A549, H1299 and H460 cells in a time-and dose-dependent manner. Western blot analysis showed that GW8510 downregulated the expression of X-linked inhibitor of apoptosis (XIAP) but had no detectable effect on the expression of Bax, Bak, or Bcl2. GW8510 also downregulated XIAP mRNA level, suggesting that downregulation of XIAP expression occurs at the transcriptional level. Moreover, ectopic XIAP expression diminished growth inhibition and apoptosis induction by GW8510. Importantly, GW8510 was not capable of inducing apoptosis of NHFB cells. These results suggest that GW8510 might provide a treatment strategy for human NSCLC and XIAP is an important target for GW8510-induced apoptosis of NSCLC cells that occurs through inhibition of XIAP mRNA transcription.
KW - Apoptosis
KW - Cyclin-dependent kinases
KW - Non-small lung cancer
KW - Small molecule
KW - X-linked inhibitor of apoptosis
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U2 - 10.4161/cbt.5.2.2316
DO - 10.4161/cbt.5.2.2316
M3 - Article
C2 - 16322690
AN - SCOPUS:33644657066
SN - 1538-4047
VL - 5
SP - 165
EP - 170
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 2
ER -