title: Calcitonin increases invasiveness of prostate cancer cells: role for cyclic AMP-dependent protein kinase A in calcitonin action.
abstract: Calcitonin (CT) is synthesized and secreted in prostate epithelium, and its secretion from malignant prostates is several-fold higher than from benign prostates. CT receptor (CTR) is expressed in malignant prostate epithelium, and its activation stimulates growth of prostate cancer (PC) cells via activation of adenylyl cyclase and calcium/phospholipid pathways. To identify the role of "CT System" in prostate cancer, we tested the expression of CT and CTR mRNAs in invading tumor cells of prostate cancer specimens. The effect of CT on in vitro invasion of PC cell lines and on activation of gelatinases was also examined. The cells of primary tumors and those invading stroma co-expressed CT/CTR mRNAs. Exogenously added CT increased in vitro invasion of PC cell lines and caused a rapid, several-fold but transient increase in protein kinase A activity. In contrast, anti-CT serum caused a dose-dependent inhibition of in vitro invasion of PC-3M cells. CT also increased the concentration and activities of MMP-2 and MMP-9. Rp.cAMP, a competitive inhibitor of cAMP-dependent protein kinase A, myristoylated protein kinase A inhibitory peptide (PKI) as well as the expression of dominant negative form of PKA all attenuated basal in vitro invasion of PC-3M cells, and CT could not increase in vitro invasiveness in their presence. These results suggest that overexpression of "CT System" in invasive PC tumors significantly contributes to increased invasiveness of prostate cancer cells. The action of CT may be mediated by protein kinase A signaling, which subsequently leads to increased cell invasion and secretion of gelatinases.
authors.affiliation: Pharmacology, University of Louisiana School of Pharmacy, College of Health Sciences, Monroe, 71209, USA.
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Sabbisetti
authors.forename: Srinivasulu
authors.initials: S
authors.lastname: Chirugupati
authors.forename: Shibu
authors.initials: S
authors.lastname: Thomas
authors.forename: Kedar S
authors.initials: KS
authors.lastname: Vaidya
authors.forename: Dean
authors.initials: D
authors.lastname: Reardon
authors.forename: Maurizio
authors.initials: M
authors.lastname: Chiriva-Internati
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Iczkowski
authors.forename: Girish V
authors.initials: GV
authors.lastname: Shah
mesh_terms: D002116:Calcitonin / Q000378:metabolism / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D018003:Receptors, Calcitonin / Q000235:genetics; D015398:Signal Transduction
chemical_list: D012333:RNA, Messenger; D018003:Receptors, Calcitonin; D002116:Calcitonin; D017868:Cyclic AMP-Dependent Protein Kinases; D020782:Matrix Metalloproteinases