Bortezomib induces apoptosis via Bim and Bik up-regulation and synergizes with cisplatin in the killing of head and neck squamous cell carcinoma cells.
Head and neck squamous cell carcinomas (HNSCC) are characterized by resistance to chemotherapy and overexpression of antiapoptotic Bcl-2 family members, including Bcl-X(L) and Bcl-2. Molecular targeting of Bcl-X(L) and/or Bcl-2 in HNSCC cells has been shown to promote apoptosis signaling and to sensitize cells to chemotherapy drugs, including cisplatin, which is commonly used in the treatment of HNSCC. We report that induction of HNSCC apoptosis by the proteasome inhibitor bortezomib is accompanied by up-regulation of the proapoptotic proteins Bik and Bim, natural cellular inhibitors of Bcl-X(L) and Bcl-2. Additionally, bortezomib treatment of HNSCC cells caused up-regulation of antiapoptotic Mcl-1L. Inhibition of Bik or Bim up-regulation using small interfering RNA markedly attenuated bortezomib-induced cell death. By contrast, small interfering RNA-mediated inhibition of Mcl-1L expression resulted in enhanced killing by bortezomib. Further investigation showed that the combination of bortezomib and cisplatin led to synergistic killing of HNSCC cells, with calculated combination indexes well below 1.0. Taken together, these results delineate a novel mechanism of HNSCC killing by bortezomib that involves up-regulation of Bik and Bik. Moreover, our findings suggest that the combination of bortezomib plus cisplatin, or bortezomib plus an inhibitor of Mcl-1L, may have therapeutic value in the treatment of HNSCC.
Departments of University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
Changyou
C
Li
Rongxiu
R
Li
Jennifer R
JR
Grandis
Daniel E
DE
Johnson
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C096820:BIK protein, human; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000069286:Bortezomib; D002945:Cisplatin