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Alpha fetoprotein is a novel protein-binding partner for caspase-3 and blocks the apoptotic signaling pathway in human hepatoma cells.
- Source :
-
International journal of cancer [Int J Cancer] 2009 Jun 15; Vol. 124 (12), pp. 2845-54. - Publication Year :
- 2009
-
Abstract
- Although there is increasing evidence that alpha fetoprotein (AFP) may function as regulatory factor in the growth of tumor cells, the precise mechanism is still unclear. In the current study, we investigated the role of the cytoplasmic AFP in caspase-3-mediated signaling of apoptosis. Our results showed that low doses of TNF-related apoptosis-inducing ligand (TRAIL) elevated the activity of caspase-8, but not caspase-3. Caspase-3 colocalized and interacted with AFP in the cytoplasm of Bel 7402 cells, and translocated into nuclei in association with the occurrence of apoptosis while cells were under cotreatment with all-trans retinoic acid (ATRA) or TRAIL. AFP was able to form complexes with caspase-3 and block onward transmission of signaling from caspase-8. Knockdown of AFP increased the sensitivity of Bel 7402 cells to TRAIL, and thereby, triggered caspase-3 signaling. No intermolecule interaction occurred between AFP and caspase-8, nor was caspase-8 activity altered after AFP knockdown, demonstrating the selectivity of AFP in interfering with the apoptotic signaling pathway. The effect of AFP on caspase-3 was further confirmed by transfection of the AFP gene into HLE cells (AFP negative). We conclude that ATRA or TRAIL resistance in AFP producing hepatoma is at least, in part, attributable to the high level of the cytoplasmic AFP. Therefore, it is possible that the combination of AFP gene silencing together with ATRA/TRAIL cotreatment will benefit the enhancement of the chemotherapeutic efficiency of these agents on tumors.<br /> (Copyright 2008 UICC.)
- Subjects :
- Antineoplastic Agents pharmacology
Blotting, Western
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular pathology
Caspase 8 metabolism
Cell Proliferation drug effects
Electrophoresis, Polyacrylamide Gel
Flow Cytometry
Fluorescence Resonance Energy Transfer
Humans
Immunoprecipitation
Liver Neoplasms drug therapy
Liver Neoplasms pathology
Protein Transport
RNA, Small Interfering pharmacology
TNF-Related Apoptosis-Inducing Ligand pharmacology
Tretinoin pharmacology
Tumor Cells, Cultured
alpha-Fetoproteins antagonists & inhibitors
alpha-Fetoproteins genetics
Apoptosis physiology
Carcinoma, Hepatocellular metabolism
Caspase 3 metabolism
Liver Neoplasms metabolism
Signal Transduction
alpha-Fetoproteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 124
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 19267404
- Full Text :
- https://doi.org/10.1002/ijc.24272