Hypoxia Promotes Synergy between Mitomycin C and Bortezomib through a Coordinated Process of Bcl-xL Phosphorylation and Mitochondrial Translocation of p53

Mol Cancer Res. 2015 Dec;13(12):1533-43. doi: 10.1158/1541-7786.MCR-15-0237. Epub 2015 Sep 9.


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.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Bortezomib / administration & dosage*
  • Bortezomib / pharmacology
  • Cell Hypoxia / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitomycin / administration & dosage*
  • Mitomycin / pharmacology
  • Phosphorylation / drug effects
  • Tumor Suppressor Protein p53 / metabolism*
  • Xenograft Model Antitumor Assays
  • bcl-X Protein / metabolism*


  • Antineoplastic Agents
  • BCL2L1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • Mitomycin
  • Bortezomib