High Glucose Induces Vascular Endothelial Growth Factor-C through Lysophosphatidic Acid Signals in Human Prostate Cancer PC-3 Cells
Date Issued
2015
Date
2015
Author(s)
Yang, Ya-Jan
Abstract
Prostate cancer is one of the most frequently diagnosed cancers in males and usually metastasizes to various organs but particularly to local lymph nodes. Clinical evidences suggest that type II diabetes mellitus has been known to increase the risk of several cancers. Hyperglycemia would increase aerobic glycolysis and promote cancer growth, but the effects on prostate cancer are still controversial. Lysophosphatidic acid (LPA) is a small glycophospholipid that mediates multiple behaviors by activating LPA receptors in cancer cells, such as cell proliferation, migration and adhesion. In our previous studies, LPA could enhance VEGF-C expression through activating LPA receptor 1/3 in prostate cancer. On the other hand, autotaxin (ATX), an enzyme responsible for LPA synthesis, was up-regulated in diabetic patients and mice. In this study, we used PC-3 cell line as a model to investigate whether high glucose induced lymphangiogenesis and aerobic glycolysis through LPA signals to drive cancer progression. Our results demonstrated that the mRNA and protein expression levels of VEGF-C and ATX were increased after 10 mM and 20 mM high glucose treatments in PC-3 cells. By pharmacological blockers and knockdown experiments, we confirmed that the expression of VEGF-C was mediated through ATX, LPA1/3, ROS and LEDGF dependent pathways. Furthermore, the mRNA and protein levels of calreticulin (CRT) were up-regulated under high glucose conditions. By knockdown experiments, we demonstrated that ATX might be a downstream signal of CRT. On the other hand, high glucose and LPA treatments also enhanced the aerobic glycolysis. Taken together, these results suggested that the abnormal glucose metabolism might lead to LPA synthesis and therefore the subsequent pathological conditions of prostate cancer. These novel findings could potentially provide new strategies for prostate cancer treatments.
Subjects
LPA
prostate cancer
aerobic glycolysis
lymphangiogenesis
VEGF-C
SDGs
Type
thesis
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