796

CALCA

calcitonin-related polypeptide alpha;CALCA;calcitonin-related polypeptide alpha

alpha-type CGRP|calcitonin|calcitonin 1|calcitonin gene-related peptide I|calcitonin/calcitonin-related polypeptide, alpha|katacalcin

11p15.2

protein-coding

The expression of human (h) calcitonin (CT) and its receptor (CTR) is localized to basal epithelium in benign prostates but is distributed in whole epithelium of malignant prostates. Moreover, the abundance of hCT and CTR mRNA in primary prostate tumors positively correlates with the tumor grade. We tested the hypothesis that the modulation of endogenous hCT expression of prostate cancer (PC) cell lines alters their oncogenicity. The effect of modulation of hCT expression on oncogenic characteristics was examined in LNCaP and PC-3M cell lines. The endogenous hCT expression was modulated using either constitutively active expression vector containing hCT cDNA or anti-hCT hammerhead ribozymes. The changes in the oncogenicity of cell sublines was assessed with cell proliferation assays, invasion assays, colony formation assays, and in vivo growth in athymic nude mice. Up-regulation of hCT in PC-3M cells and or enforced hCT expression in LNCaP cells dramatically enhanced their oncogenic characteristics. In contrast, the down-regulation of hCT in PC-3M cells led to a dramatic decline in their oncogenicity. These results, when combined with our other results, that the expression of hCT in primary PCs increase with tumor grade, suggest an important role for hCT in the progression of PC to a metastatic phenotype.

expression of calcitonin (CT) and its receptor (CTR) is elevated in advanced prostate cancer (PC). Although the significance of CT-CTR axis in PC cell growth, invasion, and epithelial to mesenchymal transition has been established, its role in tumor metastasis has not been examined. To examine the role of CT-CTR axis in tumor metastasis, we employed stable CT-CTR activated and silenced system of three PC cell lines, LNCaP cells that lack endogenous CT, PC-3 cells that lack endogenous CTR, and PC-3M cells that co-express CT and CTR. Enforced expression of CT in LNCaP cells and CTR in PC-3 cells increased their ability to form orthotopic tumors and distant metastases in multiple organs. By contrast, silencing of CT expression in PC-3M cells not only reduced their tumorigenicity, but also completely abrogated their metastatic potential. To investigate the effect of in vivo silencing of CT expression on tumor growth, we employed recombinant adeno-associated virus (rAAV) to deliver anti-CT ribozymes in preexisting tumors of nude mice and large probasin promoter (LPB)-Tag transgenic mice. rAAV-CT(-) treatment not only abrogated the growth of pre-implanted tumors in nude mice, but also significantly reduced the growth of spontaneous tumors in LPB-Tag mice. Analysis of CT upregulated and silenced PC-3M transcriptomes revealed 105 genes affected by the modulation of CT expression. These CT signature genes generated survival, adhesion, pro-inflammatory, and pro-metastatic pathways. Added together, these data indicate a pivotal role for CT-CTR axis in PC metastasis and may serve as a potential therapeutic target for advanced PC.