Hypoxia Promotes Synergy between Mitomycin C and Bortezomib through a Coordinated Process of Bcl-xL Phosphorylation and Mitochondrial Translocation of p53
| Autor: | Ashok K. Dilly, Yong J. Lee, Yong Tae Kwon, David L. Bartlett, Haroon A. Choudry, Xinxin Song |
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| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
Cell Survival Mitomycin bcl-X Protein Antineoplastic Agents Bcl-xL Article Bortezomib Mice Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Phosphorylation Protein kinase A Molecular Biology biology Tumor hypoxia Cytochrome c Mitomycin C Drug Synergism Xenograft Model Antitumor Assays Cell Hypoxia Mitochondria Gene Expression Regulation Neoplastic Oncology Apoptosis biology.protein Proteasome inhibitor Cancer research Tumor Suppressor Protein p53 Colorectal Neoplasms medicine.drug |
| Zdroj: | Molecular Cancer Research. 13:1533-1543 |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | Colorectal peritoneal carcinomatosis (CPC) exhibits severe tumor hypoxia, leading to drug resistance and disease aggressiveness. This study demonstrates that the combination of the chemotherapeutic agent mitomycin C with the proteasome inhibitor bortezomib induced synergistic cytotoxicity and apoptosis, which was even more effective under hypoxia in colorectal cancer cells. The combination of mitomycin C and bortezomib at sublethal doses induced activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase and resulted in Bcl-xL phosphorylation at Serine 62, leading to dissociation of Bcl-xL from proapoptotic Bak. Interestingly, the intracellular level of p53 became elevated and p53 translocated to the mitochondria during the combinatorial treatment, in particular under hypoxia. The coordinated action of Bcl-xL phosphorylation and p53 translocation to the mitochondria resulted in conformational activation of Bak oligomerization, facilitating cytochrome c release and apoptosis induction. In addition, the combinatorial treatment with mitomycin C and bortezomib significantly inhibited intraperitoneal tumor growth in LS174T cells and increased apoptosis, especially under hypoxic conditions in vivo. This study provides a preclinical rationale for the use of combination therapies for CPC patients. Implications: The combination of a chemotherapy agent and proteasome inhibitor at sublethal doses induced synergistic apoptosis, in particular under hypoxia, in vitro and in vivo through coordinated action of Bcl-xL and p53 on Bak activation. Mol Cancer Res; 13(12); 1533–43. ©2015 AACR. |
| Databáze: | OpenAIRE |
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