Inhibition of the PI3K/AKT signaling pathway sensitizes diffuse large B-cell lymphoma cells to treatment with proteasome inhibitors via suppression of BAG3

Proteasome inhibitors represent a novel class of drugs that have clinical efficacy against hematological and solid cancer types, including acute myeloid leukaemia, myelodysplastic syndrome an non-small cell lung cancer. It has been demonstrated that the anti-apoptotic protein B-cell lymphoma-2-associated athanogene 3 (BAG3) is induced by proteasome inhibitors in various cancer cells and serves an important role in chemotherapy resistance. The phosphatidylinositol 3-kinase (PI3K)/RAC-alpha serine/threonine-protein kinase (AKT) pathway is constitutively activated in a number of lymphoid malignancy types, including diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. In the present study, the aim was to elucidate the role of the PI3K/AKT signaling pathway in the induction of BAG3, following exposure to a proteasome inhibitor in DLBCL cell lines. Bortezomib and MG132 were used as proteasome inhibitors. Western blotting was used to evaluate the roles of proteasome inhibitors and the PI3K/AKT pathway in BAG3 induction in DLBCL cells (LY1 and LY8), and LY294002 was used to block the PI3K/AKT pathway. Cell viability was detected using a Cell Counting Kit-8 assay. Apoptosis of LY1 and LY8 cells was quantified by Annexin V/7-amino-actinomycin D flow cytometry. The BAG3 protein was markedly induced upon exposure to bortezomib and MG132 in a dose-dependent manner. The PI3K/AKT inhibitor LY294002 significantly suppressed the induction of BAG3 by proteasome inhibitors. Inhibition of the PI3K/AKT pathway decreased the proliferation and increased the apoptosis induced by proteasome inhibitors. The present results indicated that the PI3K/AKT pathway is associated with the activation of BAG3 expression in DLBCL cells, and is involved in the protective response against proteasome inhibition.