Hyperthermia-enhanced TRAIL- and mapatumumab-induced apoptotic death is mediated through mitochondria in human colon cancer cells

Xinxin Song, Han Cheon Kim, Seog Young Kim, Per Basse, Bae Hang Park, Byeong Chel Lee, Yong J. Lee*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Colorectal cancer is the third leading cause of cancer-related mortality in the world; death usually results from uncontrolled metastatic disease. Previously, we developed a novel strategy of TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) in combination with hyperthermia to treat hepatic colorectal metastases. However, previous studies suggest a potential hepatocyte cytotoxicity with TRAIL. Unlike TRAIL, anti-human TRAIL receptor antibody induces apoptosis without hepatocyte toxicity. In this study, we evaluated the anti-tumor efficacy of humanized anti-death receptor 4 (DR4) antibody mapatumumab (Mapa) by comparing it with TRAIL in combination with hyperthermia. TRAIL, which binds to both DR4 and death receptor 5 (DR5), was approximately tenfold more effective than Mapa in inducing apoptosis. However, hyperthermia enhances apoptosis induced by either agent. We observed that the synergistic effect was mediated through elevation of reactive oxygen species, c-Jun N-terminal kinase activation, Bax oligomerization, and translocalization to the mitochondria, loss of mitochondrial membrane potential, release of cytochrome c to cytosol, activation of caspases, and increase in poly(ADP-ribose) polymerase cleavage. We believe that the successful outcome of this study will support the application of Mapa in combination with hyperthermia to colorectal hepatic metastases.

Original languageEnglish (US)
Pages (from-to)1547-1558
Number of pages12
JournalJournal of Cellular Biochemistry
Volume113
Issue number5
DOIs
StatePublished - May 2012

Keywords

  • APOPTOSIS
  • Bax
  • CYTOCHROME c
  • HYPERTHERMIA
  • JNK
  • MAPATUMUMAB
  • PARP
  • ROS
  • TRAIL

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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