Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil.
The candidate tumor suppressor KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor for the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a promising agent for cancer therapy. The majority of studies on KILLER/DR5 have been focused on its role in TRAIL-induced apoptosis. However, its contribution to the inhibition of tumor growth and its role as a determinant of chemosensitivity are poorly understood. In the present study, we have generated stable human colon cancer cell lines, in which the function of KILLER/DR5 was ablated using inducible RNA interference. Inducible silencing of KILLER/DR5 in vivo by exposure of mice to doxycycline led to accelerated growth of bioluminescent tumor xenografts and conferred resistance to the chemotherapeutic agent 5-fluorouracil. Our results suggest that KILLER/DR5 may be a critical determinant for tumorigenicity and chemosensitivity.
Wang
Shulin
S
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
El-Deiry
Wafik S
WS
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D003131:Combined Modality Therapy; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D008163:Luminescent Measurements; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D034622:RNA Interference; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; C505640:Tnfrsf10b protein, mouse; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D004318:Doxycycline; D005472:Fluorouracil