Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers: Synergism with sulindac-mediated inhibition of Bcl-xL

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Abstract

The cornerstone of the systemic treatment of advanced colorectal cancer is 5-fluorouracil. However, 5-fluorouracil-induced apoptosis is dependent on p53, a tumor suppressor gene that is lost or inactivated in at least 85% of human colorectal cancers. Here we show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L triggers caspase-8-mediated truncation of BID, mitochondrial activation of caspase-9, and apoptosis in both p53+/+or p53-/-isogenic HCT116 colorectal cancer cells. TRAIL/Apo2L also sensitizes both p53+/+or p53-/-colorectal cancer cells to ionizing radiation. In contrast, we find that TRAIL/Apo2L fails to activate caspase-9 or induce apoptosis in isogenic HCT116 colorectal cancer cells that are deficient in BAX, a proapoptotic gene that is mutated in >50% of colorectal cancers of the microsatellite mutator phenotype. Loss of BAX also renders colorectal cancer cells resistant to TRAIL/Apo2L-mediated radiosensitization. We additionally demonstrate that TRAIL/Apo2L-induced death of p53+/+- or p53-/-- BAX-proficient but not BAX-deficient colorectal cancer cells is augmented by reducing nuclear factor-κB-dependent expression of Bcl-xLwith either a peptide that disrupts the inhibitor of κB kinase complex or the nonsteroidal anti- inflammatory drug, sulindac sulfide. These results indicate that the combination of TRAIL/Apo2L with either irradiation or sulindac may be highly effective against both p53-proficient and p53-deficient colorectal cancers; however, BAX-deficient tumors may evade elimination by TRAIL/Apo2L-based regimens. Our findings may aid the development and genotype-specific application of TRAIL/Apo2L-based combinatorial regimens for the treatment of colorectal cancers.

Original languageEnglish (US)
Pages (from-to)1583-1587
Number of pages5
JournalCancer Research
Volume62
Issue number6
StatePublished - Mar 15 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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