LPA1/3 signaling mediates tumor lymphangiogenesis through promoting CRT expression in prostate cancer
Journal
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Journal Volume
1863
Journal Issue
10
Pages
1305-1315
Date Issued
2018
Author(s)
Lin Y.-C.
Chen C.-C.
Chen W.-M.
Lu K.-Y.
Jou Y.-C.
Shen C.-H.
Ohbayashi N.
Kanaho Y.
Huang Y.-L.
Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid growth factor which is present in high levels in serum and platelets. LPA binds to its specific G-protein-coupled receptors, including LPA1 to LPA6, thereby regulating various physiological functions, including cancer growth, angiogenesis, and lymphangiogenesis. Our previous study showed that LPA promotes the expression of the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C in prostate cancer (PCa) cells. Interestingly, LPA has been shown to regulate the expression of calreticulin (CRT), a multifunctional chaperone protein, but the roles of CRT in PCa progression remain unclear. Here we investigated the involvement of CRT in LPA-mediated VEGF-C expression and lymphangiogenesis in PCa. Knockdown of CRT significantly reduced LPA-induced VEGF-C expression in PC-3 cells. Moreover, LPA promoted CRT expression through LPA receptors LPA1 and LPA3, reactive oxygen species (ROS) production, and phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Tumor-xenografted mouse experiments further showed that CRT knockdown suppressed tumor growth and lymphangiogenesis. Notably, clinical evidence indicated that the LPA-producing enzyme autotaxin (ATX) is related to CRT and that CRT level is highly associated with lymphatic vessel density and VEGF-C expression. Interestingly, the pharmacological antagonist of LPA receptors significantly reduced the lymphatic vessel density in tumor and lymph node metastasis in tumor-bearing nude mice. Together, our results demonstrated that CRT is critical in PCa progression through the mediation of LPA-induced VEGF-C expression, implying that targeting the LPA signaling axis is a potential therapeutic strategy for PCa. ? 2018 Elsevier B.V.
SDGs
Other Subjects
autotaxin; calreticulin; initiation factor 2alpha; lysophosphatidic acid; messenger RNA; platelet endothelial cell adhesion molecule 1; podoplanin; reactive oxygen metabolite; vasculotropin C; X box binding protein 1; alkylglycerophosphoethanolamine phosphodiesterase; COL4A3BP protein, human; initiation factor 2; lysophosphatidic acid; lysophosphatidic acid receptor; lysophospholipid; phosphodiesterase; protein serine threonine kinase; reactive oxygen metabolite; vasculotropin C; VEGFC protein, human; animal experiment; animal model; animal tissue; Article; cancer inhibition; controlled study; enzyme phosphorylation; human; human cell; immunohistochemistry; lymph node metastasis; lymph vessel; lymphangiogenesis; male; mouse; nonhuman; priority journal; prostate cancer; protein expression; tumor xenograft; Western blotting; animal; cancer transplantation; disease exacerbation; drug effect; genetics; lymphangiogenesis; metabolism; nude mouse; prostate tumor; signal transduction; tumor cell line; Animals; Cell Line, Tumor; Disease Progression; Eukaryotic Initiation Factor-2; Humans; Lymphangiogenesis; Lymphatic Metastasis; Lysophospholipids; Male; Mice; Mice, Nude; Neoplasm Transplantation; Phosphoric Diester Hydrolases; Prostatic Neoplasms; Protein-Serine-Threonine Kinases; Reactive Oxygen Species; Receptors, Lysophosphatidic Acid; Signal Transduction; Vascular Endothelial Growth Factor C
Type
journal article