Protein kinase D3 promotes gastric cancer development through p65/6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 activation of glycolysis.

Although serine/threonine-protein kinases are found to participate in a wide range of cancer progression, the involvement of protein kinase D3 (PRKD3) in gastric cancer has not been explored. Here, we investigated the role of PRKD3 in gastric cancer (GC) and its potential mechanisms. PRKD3 was over-expressed in gastric cancer tissues and cells. In vitro, PRKD3 ectopic expression accelerated the proliferation and growth of GES-1, SGC7901 and MKN-28 cells. By contrast, PRKD3 knockdown suppressed the proliferation of SGC7901 and MKN-28 GC cells. In vivo, xenograted tumorigenesis was blunted by PRKD3 silencing. Mechanistically, PRKD3 up-regulated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and activated glycolysis as shown by increased glucose consumption and lactate production. Knockdown of PFKFB3 suppressed the glycolysis in gastric cancer cells with highly expressed PRKD3 but not in PRKD3 silenced cells. PRKD3 over-expression induced phosphorylation of p65 at serine 536 was critical for the up-regulation of glycolytic enzyme PFKFB3. Furthermore, PRKD and PFKFB3 inhibitor suppressed the viability of GC cells. Our results suggest that targeting PRKD3/p65/PFKFB3 cascade maybe a promising therapeutic strategy for gastric cancer.