Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli
Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results...
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Published in | Journal of cellular physiology Vol. 227; no. 4; pp. 1319 - 1325 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.04.2012
Wiley |
Subjects | |
Online Access | Get full text |
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Summary: | Sorafenib increases survival rate of patients with advanced hepatocellular carcinoma (HCC). The mechanism underlying this effect is not completely understood. In this work we have analyzed the effects of sorafenib on autocrine proliferation and survival of different human HCC cell lines. Our results indicate that sorafenib in vitro counteracts autocrine growth of different tumor cells (Hep3B, HepG2, PLC‐PRF‐5, SK‐Hep1). Arrest in S/G2/M cell cycle phases were observed coincident with cyclin D1 down‐regulation. However, sorafenib's main anti‐tumor activity seems to occur through cell death induction which correlated with caspase activation, increase in the percentage of hypodiploid cells, activation of BAX and BAK and cytochrome c release from mitochondria to cytosol. In addition, we observed a rise in mRNA and protein levels of the pro‐apoptotic “BH3‐domain only” PUMA and BIM, as well as decreased protein levels of the anti‐apoptotic MCL1 and survivin. PUMA targeting knock‐down, by using specific siRNAs, inhibited sorafenib‐induced apoptotic features. Moreover, we obtained evidence suggesting that sorafenib also sensitizes HCC cells to the apoptotic activity of transforming growth factor‐β (TGF‐β) through the intrinsic pathway and to tumor necrosis factor‐α (TNF) through the extrinsic pathway. Interestingly, sensitization to sorafenib‐induced apoptosis is characteristic of liver tumor cells, since untransformed hepatocytes did not respond to sorafenib inducing apoptosis, either alone or in combination with TGF‐β or TNF. Indeed, sorafenib effectiveness in delaying HCC late progression might be partly related to a selectively sensitization of HCC cells to apoptosis by disrupting autocrine signals that protect them from adverse conditions and pro‐apoptotic physiological cytokines. J. Cell. Physiol. 227: 1319–1325, 2012. © 2011 Wiley Periodicals, Inc. |
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Bibliography: | NIH - No. R01CA127228; No. R37CA023226; No. R01CA074131 Ministerio de Ciencia e Innovación, Spain - No. BFU2006-01036; No. BFU2009-07219; No. ISCIII-RTICC RD06/0020 AGAUR-Generalitat de Catalunya - No. 2005SGR-00549; No. 2009SGR-312 istex:BB543A221F7F1CAE3423DC0EE9F5ECAD22313AFE ark:/67375/WNG-HPQR8ZLZ-R ArticleID:JCP22843 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0021-9541 1097-4652 1097-4652 |
DOI: | 10.1002/jcp.22843 |