Sensitization of Human Colon Cancer Cells to TRAIL-Mediated Apoptosis

Ambrosio Hernandez, Qingding Wang, Stephanie A. Schwartz, B. Mark Evers

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

TNF-related apoptosis-inducing ligand (TRAIL), a novel member of the tumor necrosis factor (TNF) family, is thought to induce apoptosis preferentially in cancer cells; however, increasing evidence suggests that a number of cancers are resistant to TRAIL treatment. FLICE-like inhibitory protein (FLIP), which structurally resembles caspase-8, can act as an inhibitor of apoptosis when expressed at high levels in certain cancer cells. The purpose of our present study was to determine whether human colon cancer cells are sensitive to TRAIL treatment and, if not, to identify potential mechanisms of resistance. Colon cancer cells of different metastatic potential (KM12C, KML4A, and KM20) were found to be resistant to the effects of TRAIL when used as a single agent. FLIP expression levels were increased in all three KM cell lines. Treatment with either actinomycin D (Act D; 10 μg/ml) or cycloheximide (CHX; 10 μg/ml) decreased FLIP expression levels in all three cell lines. The decrease in cellular levels of FLIP was associated with sensitization to TRAIL-mediated apoptosis, as demonstrated by enhanced cell death and caspase-3 activity compared with either Act D or CHX alone. Our findings suggest that reduction of FLIP levels by Act D or CHX renders TRAIL-resistant human colon cancer cells sensitive to TRAIL-mediated apoptosis. The combination of TRAIL along with agents such as Act D or CHX, which target proteins that prevent cell death, may provide a more effective and less toxic regimen for treatment of resistant colon cancers. (J GASTROINTEST SURG 2001;5:56-65.).

Original languageEnglish
Pages (from-to)56-65
Number of pages10
JournalJournal of Gastrointestinal Surgery
Volume5
Issue number1
DOIs
StatePublished - 2001

Bibliographical note

Funding Information:
From the Department of Surgery, The University of Texas Medical Branch, Galveston, Tex. Presented at the Forty-First Annual Meeting of The Society for Surgery of the Alimentary Tract, and published as an abstract in Gastroentmolog 118:A1025,2000. Supported by grants ROl AG10885, ROI DK48498, PO1 DK35608, and T32 DK07639 from the National Institutes of Health, Bethesda, Md. Reprint requests: B. Mark Evers, M.D., Department of Surgery, The University of ‘l&as Medical Branch, 301 University Blvd., Galveston, TX 77.5.55-0536. e-mail: mevers@utmb.edu

Keywords

  • Actinomycin D
  • Apoptosis
  • Colon cancers
  • Cycloheximide
  • FLIP
  • TRAIL

ASJC Scopus subject areas

  • Surgery
  • Gastroenterology

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