The Role of Cyclin E1(CCNE1) in Hepatocellular Carcinoma Treated with Sorafenib
Date Issued
2012
Date
2012
Author(s)
Cheng, Yu-Che
Abstract
Sorafenib is a drug for standard systemic therapy in patients with advanced HCC (hepatocellular carcinoma), and it is also the first drug with survival benefits. Although sorafenib was originally designed as a specific Raf kinase inhibitor, we and other investigators have found many off-target effects of sorafenib that may have significant implications regarding its anti-tumor activity and resistance mechanisms of sorafenib in HCC cells. Our laboratory has found, for example, that sorafenib can down-regulate Cyclin E1 expression in mRNA and protein levels in various HCC cell lines. The resistance of HCC cells to sorafenib is associated with higher basal levels of Cyclin E1 expression and failure by sorafenib to cause down-regulation. Knockdown of Cyclin E1 expression by siRNA reversed the resistance of HCC cells to sorafenib in terms of cell apoptosis induction. In the present study, we sought information for a more in-depth discussion of the role Cyclin E1 plays in sorafenib-resistant HCC, with particular attention to feasibility and clinical applications. In the study, I promoted the over-expression of Cyclin E1, and this was effectively able to prevent apoptosis induction by sorafenib in HCC. In exploring the clinical application of a combination of sorafenib and flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, I found that it synergistically inhibited cell growth and induced apoptosis in HCC cells. The synergistic efficacy was associated with the suppression of Bcl-XL and Mcl-1 expression in HCC cells. Finally, sorafenib combined with flavopiridol inhibited tumor growth significantly better than either agent did individually in the xenograft models. In conclusion, the results indicate that Cyclin E1 might be a potential target for cancer therapy and a candidate marker for disease diagnosis or prognosis. In addition, sorafenib combined with flavopiridol could be of potential therapeutic value in the future.
Subjects
Hepatocellular carcinoma (HCC)
off-target effects
Cyclin E1
SDGs
Type
thesis
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