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606552.pdf (1.09 MB)

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2012-04

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/126086

Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli

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https://doi.org/10.1002/jcp.22843

Resum

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-beta (TGF-beta) through the intrinsic pathway and to tumor necrosis factor-a (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-beta 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. (C) 2011 Wiley Periodicals, Inc.

Matèries

Càncer de fetge, Mort cel·lular

Matèries (anglès)

Liver cancer, Cell death

Citació

Col·leccions

Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

FERNANDO, Joan, SANCHO, Patrícia, FERNÁNDEZ RODRÍGUEZ, Conrado m., LLEDÓ, José l., CAJA PUIGSUBIRÀ, Laia, CAMPBELL, Jean s., FAUSTO, Nelson, FABREGAT ROMERO, Isabel. Sorafenib sensitizes hepatocellular carcinoma cells to physiological apoptotic stimuli. _Journal of Cellular Physiology_. 2012. Vol. 227, núm. 4, pàgs. 1319-1325. [consulta: 1 de gener de 2026]. ISSN: 0021-9541. [Disponible a: https://hdl.handle.net/2445/126086]

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