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. © 2005 Wiley‐Liss, Inc.

[1]  K. Becker,et al.  Protein kinase A isozyme switching: eliciting differential cAMP signaling and tumor reversion , 2004, Oncogene.

[2]  Kerstin Knerr,et al.  Bone metastasis: Osteoblasts affect growth and adhesion regulons in prostate tumor cells and provoke osteomimicry , 2004, International journal of cancer.

[3]  P. Ongusaha,et al.  HB-EGF Is a Potent Inducer of Tumor Growth and Angiogenesis , 2004, Cancer Research.

[4]  G. Roomans,et al.  Neuropeptides, apoptosis and ion changes in prostate cancer. Methods of study and recent developments. , 2004, Histology and histopathology.

[5]  Y. Shiratori,et al.  Vitamin K2 inhibits the growth and invasiveness of hepatocellular carcinoma cells via protein kinase A activation , 2004, Hepatology.

[6]  S. Papadakis,et al.  The development of bone metastases as the first sign of metastatic spread in patients with primary solid tumours , 2004, International Orthopaedics.

[7]  S. Mohanty,et al.  Bone marrow metastasis in solid tumors. , 2003, Indian journal of pathology & microbiology.

[8]  M. Balzi,et al.  Luteinizing hormone increases human endometrial cancer cells invasiveness through activation of protein kinase A. , 2003, Cancer research.

[9]  Sang Eun Lee,et al.  Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. , 2002, The Journal of urology.

[10]  J. Thevelein,et al.  Molecular mechanisms controlling the localisation of protein kinase A , 2002, Current Genetics.

[11]  C. Stratakis,et al.  Protein kinase A and human disease , 2002, Trends in Endocrinology & Metabolism.

[12]  E. Baldi,et al.  Endothelin‐1 production by prostate cancer cell lines is up‐regulated by factors involved in cancer progression and down‐regulated by androgens , 2001, The Prostate.

[13]  D M Essayan,et al.  Cyclic nucleotide phosphodiesterases. , 2001, The Journal of allergy and clinical immunology.

[14]  J. Chien,et al.  Calcitonin is expressed in gonadotropes of the anterior pituitary gland: its possible role in paracrine regulation of lactotrope function. , 2001, The Journal of endocrinology.

[15]  R. Fridman,et al.  Differential regulation of matrix metalloproteinase‐9, tissue inhibitor of metalloproteinase‐1 (TIMP‐1) and TIMP‐2 expression in co‐cultures of prostate cancer and stromal cells , 2001, International journal of cancer.

[16]  J. Chien,et al.  Calcitonin is a prostate epithelium-derived growth stimulatory peptide , 2001, Molecular and Cellular Endocrinology.

[17]  I. Mori,et al.  Prognostic significance of neuroendocrine differentiation, proliferation activity and androgen receptor expression in prostate cancer , 2001, Pathology international.

[18]  Mason R. Mackey,et al.  Cloning and mitochondrial localization of full-length D-AKAP2, a protein kinase A anchoring protein , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Pondel,et al.  Calcitonin and calcitonin receptors: bone and beyond , 2000, International journal of experimental pathology.

[20]  J. Baniel,et al.  Low PSA Metastatic Androgen– Independent Prostate Cancer , 2000, European Urology.

[21]  J. Overgaard,et al.  Association between immunohistochemical expression of vascular endothelial growth factor (VEGF), VEGF-expressing neuroendocrine-differentiated tumor cells, and outcome in prostate cancer patients subjected to watchful waiting. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[22]  K. Brew,et al.  Tissue inhibitors of metalloproteinases: evolution, structure and function. , 2000, Biochimica et biophysica acta.

[23]  A. Schally,et al.  Presence of receptors for bombesin/gastrin‐releasing peptide and mRNA for three receptor subtypes in human prostate cancers , 2000, The Prostate.

[24]  A. Wells,et al.  EGF receptor signaling in prostate morphogenesis and tumorigenesis. , 1999, Histology and histopathology.

[25]  J. Chien,et al.  Constitutive activation of stimulatory guanine nucleotide binding protein (GSαQL)-mediated signaling increases invasiveness and tumorigenicity of PC-3M prostate cancer cells , 1999, Oncogene.

[26]  M. Colledge,et al.  AKAPs: from structure to function. , 1999, Trends in cell biology.

[27]  Y. Furuya,et al.  Pattern of progression and survival in hormonally treated metastatic prostate cancer , 1999, International journal of urology : official journal of the Japanese Urological Association.

[28]  T. Thompson,et al.  Novel regulation of type IV collagenase (matrix metalloproteinase-9 and -2) activities by transforming growth factor-beta1 in human prostate cancer cell lines. , 1999, Molecular biology of the cell.

[29]  H. Fuse,et al.  Effect of prostatic neuropeptides on invasion and migration of PC-3 prostate cancer cells. , 1998, Cancer letters.

[30]  T. Thompson,et al.  Neuropeptides induce Mr 92,000 type IV collagenase (matrix metalloprotease-9) activity in human prostate cancer cell lines. , 1998, Cancer research.

[31]  T. Thompson,et al.  Requirement for matrix metalloproteinase-9 (gelatinase B) expression in metastasis by murine prostate carcinoma. , 1998, The American journal of pathology.

[32]  K. Morgan,et al.  Requirement for Protein Kinase C θ for Cell Cycle Progression and Formation of Actin Stress Fibers and Filopodia in Vascular Endothelial Cells* , 1997, The Journal of Biological Chemistry.

[33]  G. Fontanini,et al.  8-Chloro-cyclic AMP inhibits autocrine and angiogenic growth factor production in human colorectal and breast cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[34]  W. Rayford,et al.  Muscarinic cholinergic receptors promote growth of human prostate cancer cells , 1997, The Prostate.

[35]  D. Tindall,et al.  Effects of the calciotrophic peptides calcitonin and parathyroid hormone on prostate cancer growth and chemotaxis , 1997, The Prostate.

[36]  H. Klocker,et al.  Regulation of prostatic growth and function by peptide growth factors , 1996, The Prostate.

[37]  W. Samson,et al.  Calcitonin is a physiological inhibitor of prolactin secretion in ovariectomized female rats. , 1996, Endocrinology.

[38]  D. Djakiew,et al.  Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone , 1996, The Prostate.

[39]  G. Chejfec,et al.  Regulation of lewis lung carcinoma invasion and metastasis by protein kinase A , 1995, International journal of cancer.

[40]  G. Tortora,et al.  Differential effects of protein kinase a sub‐units on chinese‐hamster‐ovary cell cycle and proliferation , 1994, International journal of cancer.

[41]  S. Beebe,et al.  The cAMP-dependent protein kinases and cAMP signal transduction. , 1994, Seminars in cancer biology.

[42]  G. Merlo,et al.  Retroviral vector-mediated overexpression of the RII beta subunit of the cAMP-dependent protein kinase induces differentiation in human leukemia cells and reverts the transformed phenotype of mouse fibroblasts. , 1994, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[43]  Y. Cho‐Chung,et al.  Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa. , 1994, British Journal of Cancer.

[44]  W. Rayford,et al.  Calcitonin stimulates growth of human prostate cancer cells through receptor-mediated increase in cyclic adenosine 3',5'-monophosphates and cytoplasmic Ca2+ transients. , 1994, Endocrinology.

[45]  C. Logothetis,et al.  Differential effects of peptide hormones bombesin, vasoactive intestinal polypeptide and somatostatin analog RC-160 on the invasive capacity of human prostatic carcinoma cells. , 1993, The Journal of urology.

[46]  L. Deftos,et al.  Synthesis and release of calcitonin-like immunoreactivity by anterior pituitary cells: evidence for a role in paracrine regulation of prolactin secretion. , 1993, Endocrinology.

[47]  S. Døskeland,et al.  Differential expression of cAMP-kinase subunits is correlated with growth in rat mammary carcinomas and uterus. , 1992, British Journal of Cancer.

[48]  L. Liotta,et al.  Cancer metastasis and angiogenesis: An imbalance of positive and negative regulation , 1991, Cell.

[49]  Y. Cho‐Chung.  Role of cyclic AMP receptor proteins in growth, differentiation, and suppression of malignancy: new approaches to therapy. , 1990, Cancer research.

[50]  P. diSant’Agnese,et al.  The neuroendocrine prostate: characterization and quantitation of calcitonin in the human gland. , 1989, The Journal of urology.

[51]  K. Havemann,et al.  Salmon and human calcitonin like material in lung cancer. , 1985, British Journal of Cancer.

[52]  E. Dowdle,et al.  Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates. , 1980, Analytical biochemistry.

[53]  S. Zucker,et al.  Comparison of techniques for measurement of gelatinases/type IV collagenases: enzyme-linked immunoassays versus substrate degradation assays , 2005, Clinical & Experimental Metastasis.

[54]  Y. Cho‐Chung.  cAMP signaling in cancer genesis and treatment. , 2003, Cancer treatment and research.

[55]  Y. Furuya,et al.  Clinical significance of pulmonary metastases in stage D2 prostate cancer patients , 2002, Prostate Cancer and Prostatic Diseases.

[56]  J. Chien,et al.  Role of stimulatory guanine nucleotide binding protein (Gsα) in proliferation of PC‐3M prostate cancer cells , 2001, International journal of cancer.

[57]  T. H. van der Kwast,et al.  Androgen‐independent growth is induced by neuropeptides in human prostate cancer cell lines , 2000, The Prostate.

[58]  Bernhard O. Palsson,et al.  Cancer cell lines , 1999 .

[59]  P. de Souza,et al.  Enhancement of paclitaxel activity against hormone-refractory prostate cancer cells in vitro and in vivo by quinacrine. , 1997, British Journal of Cancer.

[60]  J. Vilches,et al.  In vitro characterization of bombesin and calcitonin on the proliferation of PC3, DU 145 and LNCaP cancer prostatic cell lines. , 1996, The International journal of developmental biology.

[61]  C. Bardin,et al.  Calcitonin gene expression in the rat uterus during pregnancy. , 1995, Recent progress in hormone research.

[62]  L. Deftos,et al.  Presence of calcitonin‐like immunoreactivity (iCT) in human prostate gland: Evidence for iCT secretion by cultured prostate cells , 1992, The Prostate.

[63]  G. McKnight,et al.  Expression of wild-type and mutant subunits of the cAMP-dependent protein kinase. , 1988, Cold Spring Harbor symposia on quantitative biology.