原创力文档rapamycin response in tumorigenic and non-tumorigenic hepatic cell lines雷帕霉素的反应在肿瘤发生的和非致瘤性肝细胞系.pdfVIP
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rapamycin response in tumorigenic and non-tumorigenic hepatic cell lines雷帕霉素的反应在肿瘤发生的和非致瘤性肝细胞系
Rapamycin Response in Tumorigenic and Non-
Tumorigenic Hepatic Cell Lines
1. 1. 2 3 3
Rosa H. Jimenez , Joan M. Boylan , Ju-Seog Lee , Mirko Francesconi , Gastone Castellani , Jennifer A.
1 1
Sanders , Philip A. Gruppuso *
1 Department of Pediatrics, Rhode Island Hospital and Brown University, Providence, Rhode Island, United States of America, 2 Department of Systems Biology, Division of
Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America, 3 Interdepartmental Center ‘‘L. Galvani,’’ University of
Bologna, Bologna, Italy
Abstract
Background: The mTOR inhibitor rapamycin has anti-tumor activity across a variety of human cancers, including
hepatocellular carcinoma. However, resistance to its growth inhibitory effects is common. We hypothesized that hepatic cell
lines with varying rapamycin responsiveness would show common characteristics accounting for resistance to the drug.
Methodology/Principal Findings: We profiled a total of 13 cell lines for rapamycin-induced growth inhibition. The non-
tumorigenic rat liver epithelial cell line WB-F344 was highly sensitive while the tumorigenic WB311 cell line, originally
derived from the WB-F344 line, was highly resistant. The other 11 cell lines showed a wide range of sensitivities. Rapamycin
induced inhibition of cyclin E–dependent kinase activity in some cell lines, but the ability to do so did not correlate with
sensitivity. Inhibition of cyclin E–dependent kinase activity was related to incorporation of p27Kip1 into cyclin E–containing
complexes in some but not all cell lines. Similarly, sensitivity of global protei
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