Mcl-1 downregulation sensitizes glioma to bortezomib-induced apoptosis

Zhang,Yang; Zhu,Xiaobo; Hou,Kun; Zhao,Jinchuan; Han,Zhiguo; Zhang,Xiaona

doi:10.3892/or.2015.3875

Mcl-1 downregulation sensitizes glioma to bortezomib-induced apoptosis

Authors:
- Yang Zhang
- Xiaobo Zhu
- Kun Hou
- Jinchuan Zhao
- Zhiguo Han
- Xiaona Zhang
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Affiliations: Department of Neurosurgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin, P.R. China, Department of Neurosurgery, The Traditional Chinese Medical Hospital of Gongzhuling, Gongzhuling, Jilin, P.R. China, Department of Anesthesiology, The First Affiliated Hospital of Jilin University, Changchun, Jilin, P.R. China
Published online on: March 23, 2015 https://doi.org/10.3892/or.2015.3875
Pages: 2277-2284

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Abstract

Glioma is the most aggressive form of primary brain tumor, with dismal patient outcome and no effective therapeutic approaches available. Targeting the ubiquitin-proteasome pathway has recently emerged as a potent rational anticancer strategy. Bortezomib, a specific proteasome inhibitor, has been approved for the treatment of relapsed or refractory multiple myeloma and other hematological malignancies as a single agent or as part of a combination therapy. However, bortezomib alone or in combination showed only minimal effects in the treatment of solid tumors. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein which protects tumor cells against spontaneous and chemotherapy-induced apoptosis. In multiple myeloma, specific downregulation of Mcl-1 induces apoptosis. Furthermore, previous studies demonstrated that proteasome inhibitors induce Mcl-1 accumulation that, in turn, slows down their pro-apoptotic effects, and the cell survival in multiple myeloma is highly dependent on Mcl-1. In the present study, we investigated the role of Mcl-1 downregulation in bortezomib-induced apoptosis in gliomas. We observed that bortezomib triggers caspase-3 and PARP activation, upregulates cytochrome c expression and induces apoptosis. Furthermore, we demonstrated that effective targeting of Mcl-1 in glioma cells by gene silencing technology augments the glioma cell sensitivity to bortezomib-induced apoptosis. In conclusion, the present study demonstrates that Mcl-1 plays a critical role in bortezomib-induced apoptosis. Mcl-1 inhibitor in combination with bortezomib present a promising novel strategy to trigger cell death pathways in the treatment of gliomas.

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