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 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.
Sussman
Robyn T
RT
Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Ricci
M Stacey
MS
Hart
Lori S
LS
Sun
Shi Yong
SY
El-Deiry
Wafik S
WS
D017209:Apoptosis; D045744:Cell Line, Tumor; D002469:Cell Separation; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand