PI3K δ/γ Selective Inhibitor Induces Autophagy And Apoptosis In Non-Hodgkin’s Lymphoma

PI3K is involved in cell proliferation,differentiation,and migration.It inhibits PI3K to fight tumors,inflammation and viruses.According to the regulatory properties of PI3K and the type of catalytic substrate lipids,they can be divided into three subclasses,class Ⅰ,class Ⅱ,and class Ⅲ.Class Ⅰ can be divided intoα,β,γ,δsubtypes.PI3Kδ is mainly present in lymphocytes and hematopoietic stem cells,plays an important role in regulating cell proliferation and survival,antibody production,and in antigen presentation.p110δ is important for the activation and fuction of B lymphocytes and T lymphocytes,the differentiation of T helper cells,and the regulation of T lymphocyte function.When the activity of PI3Kδ changes,hematoma and myeloid leukemia often occur.p110γ mainly exists in T lymphocytes and chronic lymphocytic leukemia cells,and regulates the inflammatory response and activation and function of chronic lymphocytic leukemia cells.When p110γmutates,it often leads to the occurrence of immune diseases.p110γplays a key role in leukocyte chemotaxis and mast cell activation.And p110γis essential for the constitutive migration and subsequent activation and differentiation of naive CD8 T cells to effector CD8 T cells and their migration to sites of inflammation.In this study,we investigated the inhibitory and regulatory mechanisms of PIK-35,a novel PI3K selectiveδ/γinhibitor,on proliferation of lymphoma cells.First,the inhibitory effect of PIK-35 on the proliferation of SU-DHL-4 cells in non-Hodgkin’s lymphoma cells was examined by a cell proliferation inhibition assay.Subsequently,the effect of PIK-35 on the apoptosis of SU-DHL-4 cells in non-Hodgkin’s lymphoma cells was analyzed using Annexin-V/FITC staining assay and flow cytometry.Western blot was used to detect the effect of PI3K-35 on apoptosis-associated proteins,and then the changes of autophagy-labeled proteins were detected by Western blot.The autophagy inhibitors 3-MA and BFA were used to treat non-Hodgkin’s and to confirm the effect of apoptosis induced by PI3K-35 on autophagy,and further examined the effect of PI3K-35 on Akt/mTOR signal transduction pathway that regulates cell apoptosis and autophagy pathways..The experimental results showed that PI3K-35 significantly inhibited the proliferation of SU-DHL-4 cells with an IC₅₀ value of 6.24μM.PI3K-35 can promote caspase3,caspase8,Caspase9,Caspase7,PARP concentration-dependent cleavage,and induce apoptosis in SU-DHL-4 cells.In addition,PI3K-35 induces the conversion of LC3-I to LC3-Ⅱ in SU-DHL-4 cells,upregulates Beclin1 expression,and induces autophagy.Further mechanistic studies have shown that PI3K-35 reduced expression of the proteins p-Akt,p-mTOR,p-4EBP1,p-P70S6K,and p-S6 in the Akt/mTOR signal transduction pathway in SU-DHL-4 cells.Autophagy induced by PI3K-35 in SU-DHL-4 cells promoted apoptosis.The above results indicate that PI3K-35 can induce autophagy and apoptosis of non-Hodgkin’s lymphoma through PI3K-regulated signal transduction pathway.The result of the study is PI3Kδ/γselective inhibitor PI3K-35 as non-Hodgkin’s lymphoma.The development of therapeutic drugs provides a scientific basis.