Hypoxia promotes synergy between mitomycin c and bortezomib through a coordinated process of Bcl-xL phosphorylation and mitochondrial translocation of p53

Xinxin Song, Ashok Kumar Dilly, Haroon Asif Choudry, David L. Bartlett, Yong Tae Kwon, Yong J. Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1533-1543
Number of pages11
JournalMolecular Cancer Research
Volume13
Issue number12
DOIs
StatePublished - Dec 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Hypoxia promotes synergy between mitomycin c and bortezomib through a coordinated process of Bcl-xL phosphorylation and mitochondrial translocation of p53'. Together they form a unique fingerprint.

Cite this