Chemotherapy-resistant side-population of colon cancer cells has a higher sensitivity to TRAIL than the non-SP, a higher expression of c-Myc and TRAIL-receptor DR4

Cancer Biol Ther. 2007 Sep;6(9):1490-5. doi: 10.4161/cbt.6.9.4905. Epub 2007 Aug 17.


Cancer stem cells are resistant to chemotherapy and provide an important target for drug development. We found that, surprisingly, the dye-effluxing side population (SP) within SW480 human colon tumor cells, a population defined to possess stem cell characteristics, expresses a 10-fold higher level of pro-apoptotic TRAIL receptor DR4 as compared to non-SP cells. The TRAIL receptors are activated by the anti-tumor host immune system through the TRAIL ligand. SW480 SP-cells express similar levels of another TRAIL receptor (DR5), as non-SP cells. SP-cells from multiple tumorigenic human cell lines, which are most often resistant to chemotherapeutic agents such as etoposide, cisplatin and 5-FU, are more sensitive to TRAIL than non-SP cells. SP-cells express higher levels of c-Myc than non-SP cells which may explain their sensitivity to TRAIL. We have found c-Myc activates DR4 transcription through E-box DNA-response elements located in the DR4 promoter, thereby increasing the expression of cell-surface pro-apoptotic death receptors in TRAIL-resistant cell lines. TRAIL sensitivity of SP-cells may represent a safeguard against malignancy, and therefore, offers a therapeutic window and opportunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Cell Line, Tumor
  • Cell Separation
  • Colonic Neoplasms / drug therapy*
  • Drug Resistance, Neoplasm*
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Microscopy, Fluorescence
  • Models, Biological
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Stem Cells / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Tumor Cells, Cultured


  • Proto-Oncogene Proteins c-myc
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand