Knock-down of calcitonin receptor expression induces apoptosis and growth arrest of prostate cancer cells.
Calcitonin (CT) and its receptor (CTR) are expressed only in basal epithelium of benign prostate and in whole epithelium of malignant prostates. Also, CT and CTR mRNA levels in prostate cancers increase with an increase in tumor grade. We tested the role of the CT/CTR autocrine axis on the tumorigenicity of prostate cancer cells. We enforced the expression of CTR in CT-positive/CTR-deficient PC-3 cells. In contrast, we knocked down CTR expression in CT/CTR-positive PC-3M cells. The effect of CTR modulation on the oncogenicity was evaluated by the rate of cell proliferation, invasion, colony formation and in vivo growth in nude mice. Up-regulation of CTR in PC-3 cells and its down-regulation in PC-3M cells significantly altered their tumorigenicity. Intratumorally administered CTR RNAi in preexisting PC-3M xenografts markedly attenuated their further growth. This treatment also led to a remarkable decrease in endothelial cell populations in the tumors and increase in apoptotic, PCNA-negative cell populations. Tumors receiving CTR RNAi treatment displayed markedly lower levels of urokinase-type plasminogen activator, phospho-Akt and survivin, suggesting CTR activates uPA-uPAR axis and PI-3-kinase-Akt-survivin pathway. These results suggest an important role for CT-CTR autocrine axis in the progression of localized prostate tumor to a metastatic phenotype, and offer a potential therapeutic option for invasive cancers.
Thomas
Shibu
S
Pharmacology, University of Louisiana School of Pharmacy, College of Health Sciences, Monroe, LA 71209, USA.
Muralidharan
A
A
Shah
Girish V
GV
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D034622:RNA Interference; D018003:Receptors, Calcitonin / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D018003:Receptors, Calcitonin; D014568:Urokinase-Type Plasminogen Activator