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

Yuan,Ting; Zhang,Feng; Zhou,Xiangxiang; Li,Ying; Zhang,Ya; Xu,Yangyang; Wang,Xin

doi:10.3892/ol.2019.10029

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

Authors:
- Ting Yuan
- Feng Zhang
- Xiangxiang Zhou
- Ying Li
- Ya Zhang
- Yangyang Xu
- Xin Wang
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Affiliations: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
Published online on: February 8, 2019 https://doi.org/10.3892/ol.2019.10029
Pages: 3719-3726
Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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‑α 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.

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