A-kinase anchoring protein 2 is required for calcitonin-mediated invasion of cancer cells

Endocr Relat Cancer. 2016 Jan;23(1):1-14. doi: 10.1530/ERC-15-0425. Epub 2015 Oct 2.

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.

Keywords: calcitonin receptor-AKAP2-prostate cancer-invasion and metastasis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / physiology*
  • Animals
  • Calcitonin / physiology*
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Receptors, Calcitonin / metabolism
  • Tumor Cells, Cultured

Substances

  • A Kinase Anchor Proteins
  • Membrane Proteins
  • Pakap protein, mouse
  • Receptors, Calcitonin
  • Calcitonin