Proliferative and metastatic roles for Phospholipase D in mouse models of cancer

Publication date: Available online 14 November 2017
Source:Advances in Biological Regulation
Author(s): Eric Roth, Michael A. Frohman
Phospholipase D (PLD) activity has been proposed to facilitate multiple steps in cancer progression including growth, metabolism, angiogenesis, and mobility. The canonical enzymes PLD1 and PLD2 enact their diverse effects through hydrolyzing the membrane lipid phosphatidylcholine to generate the second messenger and signaling lipid phosphatidic acid (PA). However, the widespread expression of PLD1 and PLD2 in normal tissues and the additional distinct enzymatic mechanisms through which PA can be generated have produced uncertainty regarding the optimal settings in which PLD inhibition might ameliorate cancer. Recent studies in mouse model systems have demonstrated that inhibition or elimination of PLD activity reduces tumor growth and metastasis. One mechanism proposed for this outcome involves proliferative signaling mediated by receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR), which is attenuated when downstream PLD signal propagation is suppressed. The reduced proliferative signaling has been reported to be compounded by dysfunctional energetic metabolism in the tumor cells under conditions of nutrient deprivation. Moreover, cancer cells lacking PLD activity display inefficiencies across multiple steps of the metastatic cascade, limiting the tumor's lethal spread. Using PLD isoform knockout mice, recent studies have reported on the net effects of inhibition and ablation in multiple cancer models through examining the role of PLD in the non-tumor cells comprising the stroma and microenvironment. The promising results of such in vivo studies, combined with the apparent low toxicity of highly-specific and potent inhibitors, highlights PLD as an attractive target for therapeutic inhibition in cancer. We discuss here the array of anti-tumor effects produced by PLD inhibition and ablation in cancer models with a focus on animal studies.



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