Calcitonin increases invasiveness of prostate cancer cells: role for cyclic AMP-dependent protein kinase A in calcitonin action.
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.
Sabbisetti
Venkata S
VS
Pharmacology, University of Louisiana School of Pharmacy, College of Health Sciences, Monroe, 71209, USA.
Chirugupati
Srinivasulu
S
Thomas
Shibu
S
Vaidya
Kedar S
KS
Reardon
Dean
D
Chiriva-Internati
Maurizio
M
Iczkowski
Kenneth A
KA
Shah
Girish V
GV
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
D012333:RNA, Messenger; D018003:Receptors, Calcitonin; D002116:Calcitonin; D017868:Cyclic AMP-Dependent Protein Kinases; D020782:Matrix Metalloproteinases