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

Research output: Contribution to journalArticle

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-xL with 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

Fingerprint

Sulindac
Colorectal Neoplasms
Apoptosis
Caspase 9
Fluorouracil
Caspase 8
Ionizing Radiation
Tumor Suppressor Genes
Microsatellite Repeats
Anti-Inflammatory Agents
Phosphotransferases
Tumor Necrosis Factor-alpha
Genotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

@article{d9b51a2cafd849498803543c0d2a7c38,
title = "Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers: Synergism with sulindac-mediated inhibition of Bcl-xL",
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-xL with 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.",
author = "Rajani Ravi and Atul Bedi",
year = "2002",
month = "3",
day = "15",
language = "English (US)",
volume = "62",
pages = "1583--1587",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - Requirement of BAX for TRAIL/Apo2L-induced apoptosis of colorectal cancers

T2 - Synergism with sulindac-mediated inhibition of Bcl-xL

AU - Ravi, Rajani

AU - Bedi, Atul

PY - 2002/3/15

Y1 - 2002/3/15

N2 - 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-xL with 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.

AB - 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-xL with 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.

UR - http://www.scopus.com/inward/record.url?scp=0037085935&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037085935&partnerID=8YFLogxK

M3 - Article

C2 - 11912124

AN - SCOPUS:0037085935

VL - 62

SP - 1583

EP - 1587

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 6

ER -