title: A-kinase anchoring protein 2 is required for calcitonin-mediated invasion of cancer cells.
abstract: Expression of neuropeptide calcitonin (CT) and its receptor (CTR) is frequently elevated in prostate cancers (PCs) and activation of CT-CTR axis in non-invasive PC cells induces an invasive phenotype. Specific, cell-permeable inhibitors of protein kinase A abolish CTR-stimulated invasion of PC cells. Since PKA is ubiquitously distributed in cells, the present study examined the mechanism(s) by which CTR-stimulated PKA activity is regulated in time and space. CT reduced cell adhesion but increased invasion of PC cells. Both these actions were abolished by st-Ht31 inhibitory peptide suggesting the involvement of an A-kinase anchoring protein (AKAP) in CT action. Next, we identified the AKAP associated with CT action by the subtraction of potential AKAP candidates using siRNAs. Knock-down of membrane-associated AKAP2, but not other AKAPs, abolished CT-stimulated invasion. Stable knock-down of AKAP2 in PC3-CTR cells remarkably decreased their cell proliferation, invasion, clonogenicity and ability to form orthotopic tumors and distant metastases in nude mice. Re-expression of AKAP2-wt restored these characteristics. Primary PC specimens displayed remarkable upregulation of CTR/AKAP2 expression as compared to benign prostates. Metastatic cancers displayed significantly higher CTR/AKAP2 expression than localized cancers. These results for the first time demonstrate that AKAP2 is expressed in human prostates, its expression is elevated in metastatic prostate cancer, and the knock-down of its expression remarkably decreased tumorigenicity and metastatic ability of prostate cancer cells. AKAP2 may serve as a critical component of CTR-mediated oncogenic actions.
authors.affiliation: PharmacologyCollege of Pharmacy, University of Louisiana, Monroe, Louisiana 71291, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Thakkar
authors.affiliation: PharmacologyCollege of Pharmacy, University of Louisiana, Monroe, Louisiana 71291, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aljameeli
authors.affiliation: PharmacologyCollege of Pharmacy, University of Louisiana, Monroe, Louisiana 71291, USA.
authors.forename: Shibu
authors.initials: S
authors.lastname: Thomas
authors.affiliation: PharmacologyCollege of Pharmacy, University of Louisiana, Monroe, Louisiana 71291, USA shah@ulm.edu.
authors.forename: Girish V
authors.initials: GV
authors.lastname: Shah
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002116:Calcitonin / Q000502:physiology*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018003:Receptors, Calcitonin / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D054758:A Kinase Anchor Proteins; D008565:Membrane Proteins; C111169:Pakap protein, mouse; D018003:Receptors, Calcitonin; D002116:Calcitonin
keywords: calcitonin receptor-AKAP2-prostate cancer-invasion and metastasis