Cadherin switching and activation of beta-catenin signaling underlie proinvasive actions of calcitonin-calcitonin receptor axis in prostate cancer.
Calcitonin, a neuroendocrine peptide, and its receptor are localized in the basal epithelium of benign prostate but in the secretory epithelium of malignant prostates. The abundance of calcitonin and calcitonin receptor mRNA displays positive correlation with the Gleason grade of primary prostate cancers. Moreover, calcitonin increases tumorigenicity and invasiveness of multiple prostate cancer cell lines by cyclic AMP-dependent protein kinase-mediated actions. These actions include increased secretion of matrix metalloproteinases and urokinase-type plasminogen activator and an increase in prostate cancer cell invasion. Activation of calcitonin-calcitonin receptor autocrine loop in prostate cancer cell lines led to the loss of cell-cell adhesion, destabilization of tight and adherens junctions, and internalization of key integral membrane proteins. In addition, the activation of calcitonin-calcitonin receptor axis induced epithelial-mesenchymal transition of prostate cancer cells as characterized by cadherin switch and the expression of the mesenchymal marker, vimentin. The activated calcitonin receptor phosphorylated glycogen synthase kinase-3, a key regulator of cytosolic beta-catenin degradation within the WNT signaling pathway. This resulted in the accumulation of intracellular beta-catenin, its translocation in the nucleus, and transactivation of beta-catenin-responsive genes. These results for the first time identify actions of calcitonin-calcitonin receptor axis on prostate cancer cells that lead to the destabilization of cell-cell junctions, epithelial-to-mesenchymal transition, and activation of WNT/beta-catenin signaling. The results also suggest that cyclic AMP-dependent protein kinase plays a key role in calcitonin receptor-induced destabilization of cell-cell junctions and activation of WNT-beta-catenin signaling.
Shah
Girish V
GV
Department of Pharmacology, University of Louisiana College of Pharmacy, Monroe, Louisiana 71209, USA. shah@ulm.edu
Muralidharan
Anbalagan
A
Gokulgandhi
Mitan
M
Soan
Kamal
K
Thomas
Shibu
S
D022005:Adherens Junctions / Q000378:metabolism; D019898:Autocrine Communication; D015820:Cadherins / Q000378:metabolism*; D002116:Calcitonin / Q000378:metabolism*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018003:Receptors, Calcitonin / Q000378:metabolism*; D015398:Signal Transduction; D019108:Tight Junctions / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D015820:Cadherins; D008565:Membrane Proteins; D010750:Phosphoproteins; D018003:Receptors, Calcitonin; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D051176:beta Catenin; D002116:Calcitonin; D038362:Glycogen Synthase Kinase 3