Accelerated degradation of caspase-8 protein correlates with TRAIL resistance in a DLD1 human colon cancer cell line

Lidong Zhang, Hongbo Zhu, Fuminori Teranishi, John J. Davis, Wei Guo, Zhen Fan, Bingliang Fang

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The tumor-selective cytotoxic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL.) makes TRAIL an attractive candidate as an anticancer agent. However, resistance to TRAIL poses a challenge in anticancer therapy with TRAIL. Therefore, characterizing the mechanisms of resistance and developing strategies to overcome the resistance are important steps toward successful TRAIL-mediated cancer therapy. In this study, we investigated mechanisms of acquired TRAIL resistance in a colon cancer DLD1 cell line. Compared with the TRAIL-susceptible DLD1 cell line, TRAIL-resistant DLD1/TRAIL-R cells have a low level of caspase-8 protein, but not its mRNA. Suppression of caspase-8 expression by siRNA in parental DLD1 cells led to TRAIL resistance. Restoration of caspase-8 protein expression by stable transfection rendered the DLD1/TRAIL-R cell line fully sensitive to TRAIL protein, suggesting that the low level of caspase-8 protein expression might be the culprit in TRAIL resistance in DLD1/TRAIL-R cells. Sequencing analysis of the caspase-8 coding region revealed a missense mutation that is present in both TRAIL-sensitive and TRAIL-resistant DLD1 cells. Subsequent study showed that the degradation of caspase-8 protein was accelerated in DLD1/TRAIL-R cells compared to parental DLD1 cells. Thus, accelerated degradation of caspase-8 protein is one of the mechanisms that lead to TRAIL resistance.

Original languageEnglish
Pages (from-to)594-602
Number of pages9
JournalNeoplasia
Volume7
Issue number6
DOIs
Publication statusPublished - Jan 1 2005
Externally publishedYes

Fingerprint

Caspase 8
Colonic Neoplasms
Cell Line
Proteins
TNF-Related Apoptosis-Inducing Ligand
Missense Mutation
Antineoplastic Agents
Small Interfering RNA
Transfection
Neoplasms
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Messenger RNA
Therapeutics

Keywords

  • Apoptosis
  • Caspase-8
  • Degradation
  • Resistance
  • TRAIL

ASJC Scopus subject areas

  • Cancer Research

Cite this

Accelerated degradation of caspase-8 protein correlates with TRAIL resistance in a DLD1 human colon cancer cell line. / Zhang, Lidong; Zhu, Hongbo; Teranishi, Fuminori; Davis, John J.; Guo, Wei; Fan, Zhen; Fang, Bingliang.

In: Neoplasia, Vol. 7, No. 6, 01.01.2005, p. 594-602.

Research output: Contribution to journalArticle

Zhang, Lidong ; Zhu, Hongbo ; Teranishi, Fuminori ; Davis, John J. ; Guo, Wei ; Fan, Zhen ; Fang, Bingliang. / Accelerated degradation of caspase-8 protein correlates with TRAIL resistance in a DLD1 human colon cancer cell line. In: Neoplasia. 2005 ; Vol. 7, No. 6. pp. 594-602.
@article{8fc72dbf31cc485dbfbc32846d3b7c4b,
title = "Accelerated degradation of caspase-8 protein correlates with TRAIL resistance in a DLD1 human colon cancer cell line",
abstract = "The tumor-selective cytotoxic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL.) makes TRAIL an attractive candidate as an anticancer agent. However, resistance to TRAIL poses a challenge in anticancer therapy with TRAIL. Therefore, characterizing the mechanisms of resistance and developing strategies to overcome the resistance are important steps toward successful TRAIL-mediated cancer therapy. In this study, we investigated mechanisms of acquired TRAIL resistance in a colon cancer DLD1 cell line. Compared with the TRAIL-susceptible DLD1 cell line, TRAIL-resistant DLD1/TRAIL-R cells have a low level of caspase-8 protein, but not its mRNA. Suppression of caspase-8 expression by siRNA in parental DLD1 cells led to TRAIL resistance. Restoration of caspase-8 protein expression by stable transfection rendered the DLD1/TRAIL-R cell line fully sensitive to TRAIL protein, suggesting that the low level of caspase-8 protein expression might be the culprit in TRAIL resistance in DLD1/TRAIL-R cells. Sequencing analysis of the caspase-8 coding region revealed a missense mutation that is present in both TRAIL-sensitive and TRAIL-resistant DLD1 cells. Subsequent study showed that the degradation of caspase-8 protein was accelerated in DLD1/TRAIL-R cells compared to parental DLD1 cells. Thus, accelerated degradation of caspase-8 protein is one of the mechanisms that lead to TRAIL resistance.",
keywords = "Apoptosis, Caspase-8, Degradation, Resistance, TRAIL",
author = "Lidong Zhang and Hongbo Zhu and Fuminori Teranishi and Davis, {John J.} and Wei Guo and Zhen Fan and Bingliang Fang",
year = "2005",
month = "1",
day = "1",
doi = "10.1593/neo.04688",
language = "English",
volume = "7",
pages = "594--602",
journal = "Neoplasia",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Accelerated degradation of caspase-8 protein correlates with TRAIL resistance in a DLD1 human colon cancer cell line

AU - Zhang, Lidong

AU - Zhu, Hongbo

AU - Teranishi, Fuminori

AU - Davis, John J.

AU - Guo, Wei

AU - Fan, Zhen

AU - Fang, Bingliang

PY - 2005/1/1

Y1 - 2005/1/1

N2 - The tumor-selective cytotoxic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL.) makes TRAIL an attractive candidate as an anticancer agent. However, resistance to TRAIL poses a challenge in anticancer therapy with TRAIL. Therefore, characterizing the mechanisms of resistance and developing strategies to overcome the resistance are important steps toward successful TRAIL-mediated cancer therapy. In this study, we investigated mechanisms of acquired TRAIL resistance in a colon cancer DLD1 cell line. Compared with the TRAIL-susceptible DLD1 cell line, TRAIL-resistant DLD1/TRAIL-R cells have a low level of caspase-8 protein, but not its mRNA. Suppression of caspase-8 expression by siRNA in parental DLD1 cells led to TRAIL resistance. Restoration of caspase-8 protein expression by stable transfection rendered the DLD1/TRAIL-R cell line fully sensitive to TRAIL protein, suggesting that the low level of caspase-8 protein expression might be the culprit in TRAIL resistance in DLD1/TRAIL-R cells. Sequencing analysis of the caspase-8 coding region revealed a missense mutation that is present in both TRAIL-sensitive and TRAIL-resistant DLD1 cells. Subsequent study showed that the degradation of caspase-8 protein was accelerated in DLD1/TRAIL-R cells compared to parental DLD1 cells. Thus, accelerated degradation of caspase-8 protein is one of the mechanisms that lead to TRAIL resistance.

AB - The tumor-selective cytotoxic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL.) makes TRAIL an attractive candidate as an anticancer agent. However, resistance to TRAIL poses a challenge in anticancer therapy with TRAIL. Therefore, characterizing the mechanisms of resistance and developing strategies to overcome the resistance are important steps toward successful TRAIL-mediated cancer therapy. In this study, we investigated mechanisms of acquired TRAIL resistance in a colon cancer DLD1 cell line. Compared with the TRAIL-susceptible DLD1 cell line, TRAIL-resistant DLD1/TRAIL-R cells have a low level of caspase-8 protein, but not its mRNA. Suppression of caspase-8 expression by siRNA in parental DLD1 cells led to TRAIL resistance. Restoration of caspase-8 protein expression by stable transfection rendered the DLD1/TRAIL-R cell line fully sensitive to TRAIL protein, suggesting that the low level of caspase-8 protein expression might be the culprit in TRAIL resistance in DLD1/TRAIL-R cells. Sequencing analysis of the caspase-8 coding region revealed a missense mutation that is present in both TRAIL-sensitive and TRAIL-resistant DLD1 cells. Subsequent study showed that the degradation of caspase-8 protein was accelerated in DLD1/TRAIL-R cells compared to parental DLD1 cells. Thus, accelerated degradation of caspase-8 protein is one of the mechanisms that lead to TRAIL resistance.

KW - Apoptosis

KW - Caspase-8

KW - Degradation

KW - Resistance

KW - TRAIL

UR - http://www.scopus.com/inward/record.url?scp=22044441646&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=22044441646&partnerID=8YFLogxK

U2 - 10.1593/neo.04688

DO - 10.1593/neo.04688

M3 - Article

C2 - 16036110

AN - SCOPUS:22044441646

VL - 7

SP - 594

EP - 602

JO - Neoplasia

JF - Neoplasia

SN - 1522-8002

IS - 6

ER -