Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells

Makiko Taniai, Annette Grambihler, Hajime Higuchi, Nate Werneburg, Steve F. Bronk, Daniel J. Farrugia, Scott H Kaufmann, Gregory James Gores

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

Cholangiocarcinomas are usually fatal neoplasms originating from bile duct epithelia. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for cancer therapy, including cholangiocarcinoma. However, many cholangiocarcinoma cells are resistant to TRAIL-mediated apoptosis. Thus, our aim was to examine the intracellular mechanisms responsible for TRAIL resistance in human cholangiocarcinoma cell lines. Three TRAIL-resistant human cholangiocarcinoma cell lines were identified. All of the cell lines expressed TRAIL receptor 1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5. Expression of TRAIL decoy receptors and the antiapoptotic cellular FLICE-inhibitory protein (cFLIP) was inconsistent across the cell lines. Of the antiapoptotic Bcl-2 family of proteins profiled (Bcl-2, Bcl-xL, and Mcl-1), Mcl-1 was uniquely overexpressed by the cell lines. When small-interfering-RNA (siRNA) technology was used to knock down expression of Bcl-2, Bcl-xL, and Mcl-1, only the Mcl-1-siRNA sensitized the cells to TRAIL-mediated apoptosis. In a cell line stably transfected with Mcl-1-small-hairpin-RNA (Mcl-1-shRNA), Mcl-1 depletion sensitized cells to TRAIL-mediated apoptosis despite Bcl-2 expression. TRAIL-mediated apoptosis in the stably transfected cells was associated with mitochondrial depolarization, Bax activation, cytochrome c release from mitochondria, and caspase activation. Finally, flavopiridol, an anticancer drug that rapidly down-regulates Mcl-1, also sensitized cells to TRAIL cytotoxicity. In conclusion, these studies not only demonstrate that Mcl-1 mediates TRAIL resistance in cholangiocarcinoma cells by blocking the mitochondrial pathway of cell death but also identify two strategies for circumventing this resistance.

Original languageEnglish (US)
Pages (from-to)3517-3524
Number of pages8
JournalCancer Research
Volume64
Issue number10
DOIs
StatePublished - May 15 2004

Fingerprint

Cholangiocarcinoma
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Cell Line
TNF-Related Apoptosis-Inducing Ligand Receptors
Small Interfering RNA
alvocidib
Tumor Necrosis Factor Decoy Receptors
CASP8 and FADD-Like Apoptosis Regulating Protein
Bile Duct Neoplasms
Caspases
Cytochromes c
Mitochondria
Cell Death
Down-Regulation
Epithelium
Technology
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells. / Taniai, Makiko; Grambihler, Annette; Higuchi, Hajime; Werneburg, Nate; Bronk, Steve F.; Farrugia, Daniel J.; Kaufmann, Scott H; Gores, Gregory James.

In: Cancer Research, Vol. 64, No. 10, 15.05.2004, p. 3517-3524.

Research output: Contribution to journalArticle

Taniai, Makiko ; Grambihler, Annette ; Higuchi, Hajime ; Werneburg, Nate ; Bronk, Steve F. ; Farrugia, Daniel J. ; Kaufmann, Scott H ; Gores, Gregory James. / Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells. In: Cancer Research. 2004 ; Vol. 64, No. 10. pp. 3517-3524.
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AU - Grambihler, Annette

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AU - Werneburg, Nate

AU - Bronk, Steve F.

AU - Farrugia, Daniel J.

AU - Kaufmann, Scott H

AU - Gores, Gregory James

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