PTEN/PI3K/AKT Signal Pathway Regulate The Resistance Of Rituximab In Lymphoma

BackgroundThe rituximab can be described the most effective,successful,and widely used therapeutic monoclonal antibody for Non-Hodgkin lymphoma(NHL)developed to date.Nonethless,as with any antineoplastic agent,the effectiveness of rituximab is ultimately limited in part by the development of treatment resistance.Although wide-spread clinical use,the mechanisms by which tumor cells resist rituximab-mediated destruction remain unclear.PTEN,as a new antineoplastic gene,can exert its tumor suppression effect through suppressing PI3K/AKT pathway.Objective1.To detect the expression of PTEN in both DLBCL tissue and normal control specimens,and analysis of the relationship between PTEN expression and the mechanism of rituximab resistance.Further to study the role of PTEN/PI3K/AKT pathway in the rituximab resistance.2.To investigate the effects of the specific inhibitor of phosphatidylinositol 3-kinase(PI3K)LY294002,on the proliferation and apoptosis of rituximab-resistance cell lines of B cell lymphoma,and on the expressions of PTEN/PI3K/AKT signaling pathway-related proteins.Furthermore,the role of PTEN/PI3K/AKT pathway in the rituximab resistance is demonstrated by another way.Methods1.To evaluate the association between PTEN and efficacy of rituximab therapy in Non-Hodgkin lymphoma by detecting the expression levels of PTEN in lymphoma tissues treated with rituximab effectively or ineffectively,through immunohistochemical(IHC)and fluorescent in situ hybridization(FISH).2.Rituximab-resistance cell lines were cultured with different concentrations of LY294002 and the same concentration of rituximab.Cell growth was determined by CCK8.Cell apoptosis was analyzed by flow cytometry.The expressions of PTEN/PI3K/AKT signaling pathway-related proteins(PTEN,PI3 K,AKT,BCL-2,Casepase-3 and Casepase-9)were detected by Western blot.Results1.Immunohistochemistry showed that the deletion expression rate of PTEN in diffuse large B cell lymphoma could reach to 31.3%,and significantly higher than the reactive hyperplasia lymph nodes and the rituximab-sensitive lymphoma tissues,the difference has statistically significant(P<0.05).2.LY294002 could enhance the sensitiveness of rituximab-resistance of B cell lines to rituximab.The difference has statistically significant(P<0.05).Conclusion1.The positive expression rate of PTEN in rituximab-resistance diffuse large B cell lymphomas is significantly lower than the reactive hyperplasia lymph nodes and the rituximab-sensitiveness lymphomas.Suggesting that expression of PTEN in DLBCL was closely associated with the mechanism of rituximab resistance.To provide a basic theory on rituximab resistance and find a new marker to predicate the effectiveness of rituximab.2.LY294002 can assist rituximab in suppressing the growth and promote the apoptosis of rituximab-resistance lymphoma cell lines by specifically inhibiting the PI3K/AKT signaling pathway.To explore the mechanism of rituximab resistance in vitro and demonstrate the association between PTEN/PI3K/AKT signaling pathway and rituximab resistance in Non-hodgkin lymphoma by another way.