Inducible release of TRAIL fusion proteins from a proapoptotic form for tumor therapy.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill neoplastic cells and control of its activity could enhance tumor therapy. We have developed means to control the secretion of a novel recombinant (r) TRAIL fusion protein using a viral protease. This system uses the endoplasmic reticulum (ER) as a storage depot for rTRAIL, because TRAIL acts by binding to its cognate receptors on the cell surface. We have engineered two TRAIL variants: (a) a secretable form that enhances apoptosis via a bystander effect; and (b) an ER-targeted TRAIL that is retained in the ER until selectively released by the viral protease. Gene delivery can be monitored in vivo by systemic administration of a near infrared fluorescent (NIRF) probe activated by the protease. This study serves as a template for design of recombinant proteins to enhance and control apoptosis of tumor cells via specific viral proteases and for use of viral proteases as in vivo reporters for cancer therapy.
Shah
Khalid
K
Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. kshah@helix.mgh.harvard.edu
Tung
Ching-Hsuan
CH
Yang
Katherine
K
Weissleder
Ralph
R
Breakefield
Xandra O
XO
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002522:Chlorocebus aethiops; D010450:Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000502:physiology; D019265:Spectroscopy, Near-Infrared; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D010450:Endopeptidases