Abstract 482: Signaling Lipid Lysophosphatidic Acid Is a Critical Link to Diet-induced Obesity, Cellular Bioenergetics and Breast Cancer Angiogenesis
Arteriosclerosis, Thrombosis, and Vascular Biology(2015)
Abstract
Background: Obesity increases breast cancer (BC) risk but mechanisms by which obesity promotes BC progression remain largely unknown. Nutritional obesity is accompanied by increasing phospholipid lysophosphatidic acid (LPA), which stimulates angiogenesis by turning off CD36 antiangiogenic switch in microvascular endothelial cells (MVECs) via protein kinase D (PKD-1) signaling pathway that was reported to regulate mitochondrial function. CD36 impacts cellular energy metabolism as it is known to function as a fatty acid transporter. Hypothesis Obesity-derived LPA promotes angiogenesis and BC progression by modifying mitochondrial bioenergetics in cancer and endothelial cells via PKD-1 signaling. Methods: MVECs and breast adenocarcinoma cells were used for elucidating key signaling pathway and detecting mitochondrial respiration. BC angiogenesis model was established in diet-induced obese and lean mice. Results: LPA enhanced mitochondrial respiration in breast adenocarcinoma cells transduced with PKD-1, leading to elevations in oxygen consumption rate (OCR) and ATP-linked OCR, but not in extracellular acidification rate (ECAR). The cancer cells exposed to conditional medium from MVECs transduced with PKD-1 showed reduced level of basal OCR, ATP-linked OCR, and ECAR. Tumor-associated ECs exposed to LPA decreased CD36 expression whereas LPA exposure reduced not only basal OCR and ATP-linked mitochondrial respiration but also basal ECAR. Overexpressing PKD-1 also reduced basal OCR and ATP-linked mitochondrial respiration in these cells. In syngeneic breast adenocarcinoma model, BC grew larger in diet induced obese mice when compared with that in lean controls (p < 0.01). The tumor endothelium in diet-induced obese mice showed increased LPA receptor 1 expression, along with reduced CD36 expression and enhanced PKD-1 phosphorylation. Concurrently, the quantity of periphery vessels was increased, with elevations in plasma level of angiogenic proteins leptin and PAI 1. Conclusion: LPA/PKD-CD36 signaling may regulate angiogenesis and promote BC progression by controlling mitochondrial respiration via modulating cellular bioenergetics. Targeting LPA/PKD-CD36-metabolic signaling axis might provide a novel therapeutic strategy.
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Key words
lipid lysophosphatidic acid,obesity,breast cancer angiogenesis,diet-induced
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