Protein kinase D2 regulates chromogranin A secretion in human BON neuroendocrine tumour cells

• Published in: Cellular signalling 2008-05, Vol.20 (5), p.925-934
• Main Authors: von Wichert, Götz, Edenfeld, Teresa, von Blume, Julia, Krisp, Holger, Krndija, Denis, Schmid, Heidrun, Oswald, Franz, Lother, Ulrike, Walther, Paul, Adler, Guido, Seufferlein, Thomas
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Base Sequence; Biological Transport, Active; Cell Line, Tumor; Chromogranin A; Chromogranin A - metabolism; Golgi Apparatus - physiology; Humans; Molecular Sequence Data; Neuroendocrine Tumors - enzymology; Neuroendocrine Tumors - metabolism; Neuroendocrine tumours; Protein Kinase D2; Protein Kinase Inhibitors - pharmacology; Protein Kinases - genetics; Protein Kinases - metabolism; Regulated transport; RNA, Small Interfering - genetics; Secretory Vesicles - physiology; Signal Transduction; trans-Golgi Network - physiology
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2008.01.003

Chromogranin A is a member of the granin family of acidic secretory glycoproteins that is found in secretory granules of many endocrine cells including neuroendocrine tumour cells. This hormone serves as a model system for autonomous hormone secretion by the so called functional neuroendocrine tumours of the gastrointestinal tract. The precise regulation of chromogranin secretion at the level of the Golgi apparatus is a subject of intense research. The protein kinase D (PKD) family of serine threonine kinases has so far been implicated in the regulation of constitutive secretion in epithelial cells. Here we examined whether PKD2 expression and activity could also play a role in the release of secretory granules from the trans Golgi network (TGN) in neuroendocrine tumour cells and hence be a target to block autonomous secretion by these tumours. Our data show that expression and catalytic activity of PKD2 are required for the release of chromogranin A containing secretory vesicles. Inhibition of PKD2 activity or siRNA knockdown of PKD2 resulted in a marked perinuclear retention of chromogranin A immunofluorescence in the trans Golgi network and led to a marked reduction in basal as well as phorbol ester stimulated secretion of chromogranin A into the supernatant of cells. Thus, PKD2 controls the release of secretory granules in neuroendocrine tumour cells at the level of the Golgi apparatus and could hence serve as a novel target to block hormone secretion in functional neuroendocrine tumours.