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Dovitinib sensitizes hepatocellular carcinoma cells to TRAIL and tigatuzumab, a novel anti-DR5 antibody, through SHP-1-dependent inhibition of STAT3.
- Source :
-
Biochemical pharmacology [Biochem Pharmacol] 2012 Mar 15; Vol. 83 (6), pp. 769-77. Date of Electronic Publication: 2012 Jan 02. - Publication Year :
- 2012
-
Abstract
- Hepatocellular carcinoma (HCC) often displays resistance to recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Dovitinib, a multiple tyrosine kinase inhibitor, and tigatuzumab, a novel humanized anti-human death receptor 5 (DR5) agonistic antibody, are both under clinical investigations in HCC. Here, we report that dovitinib sensitizes resistant HCC cells to TRAIL- and tigatuzumab-induced apoptosis through inhibition of signal transducers and activators of transcription 3 (STAT3). Our data indicate that HCC cells showed significant resistance to TRAIL- and tigatuzumab-induced apoptosis. The combination of dovitinib and tigatuzumab restored the sensitivity of HCC cells to TRAIL- and tigatuzumab-induced apoptosis. Dovitinib down-regulated phospho-STAT3 (Tyr705) (p-STAT3) and subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, in TRAIL-treated HCC cells. Knockdown of STAT3 by RNA-interference overcame apoptotic resistance to TRAIL in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effect of dovitinib on TRAIL-induced apoptosis. Importantly, silencing SHP-1 by RNA-interference reduced the effects of dovitinib and TRAIL on p-STAT3 and apoptosis, whereas co-treatment of TRAIL and dovitinib increased the activity of SHP-1. Moreover, in vivo the combination of tigatuzumab and dovitinib inhibited Huh-7 xenograft tumor growth. In conclusion, dovitinib sensitizes resistant HCC cells to TRAIL- and tigatuzumab-induced apoptosis through a novel machinery: SHP-1 dependent STAT3 inhibition.<br /> (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Combined Chemotherapy Protocols pharmacology
Apoptosis drug effects
Cell Line, Tumor
Cyclin D1 antagonists & inhibitors
Cyclin D1 metabolism
Down-Regulation
Humans
Inhibitor of Apoptosis Proteins antagonists & inhibitors
Inhibitor of Apoptosis Proteins metabolism
Male
Mice
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein
Protein Tyrosine Phosphatase, Non-Receptor Type 6 antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 6 metabolism
Protein-Tyrosine Kinases antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand antagonists & inhibitors
STAT3 Transcription Factor antagonists & inhibitors
STAT3 Transcription Factor metabolism
Survivin
Antibodies, Monoclonal, Humanized pharmacology
Antineoplastic Agents pharmacology
Benzimidazoles pharmacology
Carcinoma, Hepatocellular metabolism
Drug Resistance, Neoplasm drug effects
Liver Neoplasms metabolism
Protein Kinase Inhibitors pharmacology
Quinolones pharmacology
TNF-Related Apoptosis-Inducing Ligand pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2968
- Volume :
- 83
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Biochemical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 22230479
- Full Text :
- https://doi.org/10.1016/j.bcp.2011.12.035