RESUMO
Alpha fetoprotein (AFP) is a highly expressed protein during fetal development. It’ s a shuttle protein that transports nutrients to embryonic cells. Similarly, during the development of malignant tumors such as liver cancer, tumor cells also express high levels of AFP and its receptors. They uptake AFP and its delivered substances through AFP receptors. Therefore, AFP can be combined with anticancer drugs to attack tumor cells selectively. There are several ways of AFP to deliver drugs, which can be noncovalently bound with drugs, and the drugs are wrapped in the hydrophobic pocket of AFP; they can also combine with drugs through covalent bonds, or use AFP to connect with nanoparticles and liposomes to improve the effect of drug delivery. AFP delivered drugs can be effectively released in the low pH environment of cancer cells. In order to avoid the risk of AFP carcinogenesis, drugs can be delivered by modifying AFP or using AFP fragments. Because AFP delivered drugs targeting therapy mainly attacks cancer cells that expressed AFP receptor, it has little effect on normal cells. AFP delivred drugs can not only promote the absorption of drugs by tumor cells, enhance the anti-cancer activity of drugs, but also overcome the problem of multidrug resistance (MDR). In addition, studies have found that AFP delivered drugs also have the effect of immunotherapy. AFP delivered drugs can not only activate T cell receptors, eliminate immune tolerance and inhibit tumor growth, but also inhibit myeloid derived suppressor cells (MDSCs), activate NK cells and T cells, thus destroying cancer cells and preventing cancer stem cell metastasis. Therefore, AFP delivery of drug is a new therapy combining immunotherapy and targeted chemotherapy, and it may become a strategy for cancer treatment in the future.
RESUMO
<p><b>OBJECTIVE</b>To explore the mechanism of Alpha-fetoprotein (AFP) effects on hepatocellular carcinoma cells (HCC) resistances apoptosis induced by tumor necrosis factor-related apoptosis inducing-ligand (TRAIL).</p><p><b>METHODS</b>The expressed alteration of TRAIL receptor-2 (DR5) after the human hepatoma cells line Bel 7402 (AFP-producing) and HLE cells (non-AFP producing) were treated with all trans retinoic acid (ATRA) were determined by Western blot; Interaction of AFP with RAR-beta was analyzed by co-immunoprecipitation (Co-IP); Laser confocal microscopy was used to observe co-localization of AFP and RAR-beta; Short small RNA interfering (RNAi) was applied to knock down the expression of AFP in Bel 7402 cells; The full AFP gene cDNA was inserted into pcDNA3.1 vector and constructed the expressed vector of AFP (named pcDNA3.1-afp); The growth of hepatoma cells was analyzed by MTT.</p><p><b>RESULTS</b>Bel 7402 and HLE cells expressed DR5, lowed dosage of ATRA (40mumol/L) had no influence on the expression of DR5 in Bel 7402 cells, but ATRA (160mumol/L) could inhibit the expression of AFP and promote the expression of DR5 significantly; Co-IP indicated that AFP had a property for interacting with RAR-beta; The results also demonstrated AFP co-localization with RAR-beta in cytoplasm of Bel 7202 cells; The expression of DR5 was enhanced while the expression of AFP was knocked down by RNAi. pcDNA3.1-afp vector was transfected into HLE cells, the growth of HLE cells were stimulated and TRAIL cytotoxicity of HLE cells were reduced. But when the expression of AFP was knocked down the sensitivity of Bel 7402 cells to TRAIL was enhanced.</p><p><b>CONCLUSIONS</b>These data provided that AFP had a capability to interact with RAR-beta and suppressed the expression of DR5. AFP could play pivotal role on hepatoma cells resistance-induced apoptosis by TRAIL.</p>