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Structural basis for alpha fetoprotein‐mediated inhibition of caspase‐3 activity in hepatocellular carcinoma cells
Author(s) -
Lin Bo,
Zhu Mingyue,
Wang Wenting,
Li Wei,
Dong Xu,
Chen Yi,
Lu Yan,
Guo Junli,
Li Mengsen
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30850
Subject(s) - alpha fetoprotein , biology , carcinogenesis , signal transduction , apoptosis , cancer research , caspase 3 , caspase , microbiology and biotechnology , hepatocellular carcinoma , chemistry , biochemistry , programmed cell death , gene
Alpha‐fetoprotein (AFP) is an early serum growth factor in the foetal liver development and hepatic carcinogenesis; However, the precise biological role of cytoplasmic AFP remains elusive. Although we recently demonstrated that cytoplasmic AFP might interact with caspase‐3 and inhibit the signal transduction of apoptosis in human hepatocellular carcinoma (HCC) cells, the details of this interaction are not clear. To reveal the molecular relationship between AFP and caspase‐3, we performed molecular docking, co‐immunoprecipitation (Co‐IP), laser confocal microscopy, site‐directed mutagenesis and functional experiments to analyse the key amino acid residues in the binding site of caspase‐3. The results of Co‐IP, laser confocal microscopy and functional analyses were consistent with the computational model. We also used the model to explain why AFP cannot bind to caspase‐8. These results provide the molecular basis for the AFP‐mediated inhibition of caspase‐3 activity in HCC cells. Altogether, we found that AFP interacts with caspase‐3 through precise amino acids, namely loop‐4 residues Glu‐248, Asp‐253 and His‐257. The results further demonstrated that AFP plays a critical role in the inhibition of the apoptotic signal transduction that mediated by caspase‐3. Thus, AFP might represent a novel biotarget for the therapy of HCC patients.