Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer.
Radioiodide is an effective therapy for thyroid cancer. This treatment modality exploits the thyroid-specific expression of the sodium iodide symporter (NIS) gene, which allows rapid internalization of iodide into thyroid cells. To test whether a similar treatment strategy could be exploited in nonthyroid malignancies, we transfected non-small cell lung cancer (NSCLC) cell lines with the NIS gene. Although the expression of NIS allowed significant radioiodide uptake in the transfected NSCLC cell lines, rapid radioiodide efflux limited tumor cell killing. Because thyroperoxidase (TPO) catalyzes iodination of proteins and subsequently causes iodide retention within thyroid cells, we hypothesized that coexpression of both NIS and TPO genes would overcome this deficiency. Our results show that transfection of NSCLC cells with both human NIS and TPO genes resulted in an increase in radioiodide uptake and retention and enhanced tumor cell apoptosis. These findings suggest that single gene therapy with only the NIS gene may have limited efficacy because of rapid efflux of radioiodide. In contrast, the combination of NIS and TPO gene transfer, with resulting TPO-mediated organification and intracellular retention of radioiodide, may lead to more effective tumor cell death. Thus, TPO could be used as a therapeutic strategy to enhance the NIS-based radioiodide concentrator gene therapy for locally advanced lung cancer.
Huang
M
M
Pulmonary Immunology and Gene Medicine Laboratory, Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCLA and VA Greater Heathcare System, Los Angeles, California 90073, USA. minhuang@ucla.edu
Batra
R K
RK
Kogai
T
T
Lin
Y Q
YQ
Hershman
J M
JM
Lichtenstein
A
A
Sharma
S
S
Zhu
L X
LX
Brent
G A
GA
Dubinett
S M
SM
D017209:Apoptosis; D015139:Blotting, Southern; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D017931:DNA Primers / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism; D007457:Iodine Radioisotopes / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D015530:Nuclear Matrix / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000528:radiation effects; D000099209:Sodium-Iodide Symporters
D017931:DNA Primers; D004791:Enzyme Inhibitors; D007453:Iodide Peroxidase; D007457:Iodine Radioisotopes; D013449:Sulfonamides; D027981:Symporters; D000099209:Sodium-Iodide Symporters