High Glucose Induces VEGF-C Expression via the LPA(1/3)-Akt-ROS-LEDGF Signaling Axis in Human Prostate Cancer PC-3 Cells
Journal
Cellular Physiology and Biochemistry
Journal Volume
50
Journal Issue
2
Pages
612-628
Date Issued
2018
Author(s)
Abstract
Background/Aims: Hyperglycemia has been shown to increase the incidence and metastasis in various types of cancers. However, the correlation between hyperglycemia and lymphatic metastasis in prostate cancer (PCa) remains unclear. Our previous study demonstrated that lysophosphatidic acid (LPA) enhances vascular endothelial growth factor-C (VEGF-C) expression, a lymphangiogenic factor, through activating it receptors LPA 1/3 in prostate cancer (PCa) cells. Moreover, hyperglycemia up-regulates autotaxin (ATX) expression, a LPA-generating enzyme. Therefore, we propose that high glucose promotes VEGF-C expression through LPA signaling in PCa cells. Methods: Pharmacological inhibitors and siRNAs were utilized to investigate the molecular mechanism of high glucose-induced VEGF-C expression. Real-time PCR and Western blot were used to determine the mRNA and protein expressions, respectively. Cellular bioenergetics analysis was performed to determine the glycolysis levels. Results: We demonstrated that the expressions of VEGF-C, ATX, and calreticulin were increased upon high glucose treatments in PC-3 cells. Moreover, high glucose-induced VEGF-C expression was mediated through the LPA 1/3 , PLC, Akt, ROS and LEDGF-dependent pathways. Additionally, high glucose enhanced the aerobic glycolysis via LPA 1/3 . Conclusion: These results indicated that hyperglycemia leads to LPA synthesis, and subsequent promoting pathological consequence of PCa. These novel findings could potentially provide new strategies for PCa treatments. ? 2018 The Author(s).
Subjects
Hyperglycemia; Lymphangiogenesis; Lysophosphatidic acid; Prostate cancer; Vascular endothelial growth factor-C
SDGs
Other Subjects
autotaxin; calreticulin; glucose; lens epithelium derived growth factor; lysophosphatidic acid; lysophosphatidic acid 1; lysophosphatidic acid 3; messenger RNA; protein kinase B; reactive oxygen metabolite; short hairpin RNA; small interfering RNA; unclassified drug; vasculotropin C; alkylglycerophosphoethanolamine phosphodiesterase; calreticulin; glucose; lens epithelium-derived growth factor; lysophosphatidic acid; lysophosphatidic acid receptor; lysophospholipid; phosphatidylinositol 4,5 bisphosphate phosphodiesterase; phosphodiesterase; protein kinase B; reactive oxygen metabolite; signal peptide; vasculotropin C; aerobic glycolysis; Article; bioenergy; cell function; cellular parameters; controlled study; extracellular acidification rate; gene expression; glucose metabolism; human; human cell; hyperglycemia; lymphangiogenesis; male; molecular dynamics; oxygen consumption rate; PC-3 cell line; phospholipid synthesis; priority journal; prostate cancer cell line; protein expression; real time polymerase chain reaction; signal transduction; upregulation; Western blotting; antagonists and inhibitors; drug effect; genetics; glycolysis; metabolism; oxygen consumption; pathology; prostate tumor; RNA interference; signal transduction; tumor cell line; Calreticulin; Cell Line, Tumor; Glucose; Glycolysis; Humans; Intercellular Signaling Peptides and Proteins; Lysophospholipids; Male; Oxygen Consumption; Phosphoinositide Phospholipase C; Phosphoric Diester Hydrolases; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Receptors, Lysophosphatidic Acid; RNA Interference; RNA, Small Interfering; Signal Transduction; Up-Regulation; Vascular Endothelial Growth Factor C
Type
journal article