title: Mcl-1 downregulation sensitizes glioma to bortezomib-induced apoptosis.
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.
authors: Department of Neurosurgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors: Yang
authors: Y
authors: Zhang
authors: Department of Neurosurgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors: Xiaobo
authors: X
authors: Zhu
authors: Department of Neurosurgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors: Kun
authors: K
authors: Hou
authors: Department of Neurosurgery, The First Affiliated Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors: Jinchuan
authors: J
authors: Zhao
authors: Department of Neurosurgery, The Traditional Chinese Medical Hospital of Gongzhuling, Gongzhuling, Jilin, P.R. China.
authors: Zhiguo
authors: Z
authors: Han
authors: Department of Anesthesiology, The First Affiliated Hospital of Jilin University, Changchun, Jilin, P.R. China.
authors: Xiaona
authors: X
authors: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D000069286:Bortezomib / Q000494:pharmacology*; D053148:Caspase 3 / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D020868:Gene Silencing; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics; D005910:Glioma / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000069286:Bortezomib; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3