Lysophosphatidic Acid Signaling in Cancer Cells: What Makes LPA So Special?

Abstract

Lysophosphatidic acid (LPA) refers to a family of simple phospholipids that act as ligands for G protein-coupled receptors. While LPA exerts effects throughout the body in normal physiological circumstances, its pathological role in cancer is of great interest from a therapeutic viewpoint. The numerous LPA receptors (LPARs) are coupled to a variety of G proteins, and more than one LPAR is typically expressed on any given cell. While the individual receptors signal through conventional GPCR pathways, LPA is particularly efficacious in stimulating cancer cell proliferation and migration. This review addresses the mechanistic aspects underlying these pro-tumorigenic effects. We provide examples of LPA signaling responses in various types of cancers, with an emphasis on those where roles have been identified for specific LPARs. While providing an overview of LPAR signaling, these examples also reveal gaps in our knowledge regarding the mechanisms of LPA action at the receptor level. The current understanding of the LPAR structure and the roles of LPAR interactions with other receptors are discussed. Overall, LPARs provide insight into the potential molecular mechanisms that underlie the ability of individual GPCRs (or combinations of GPCRs) to elicit a unique spectrum of responses from their agonist ligands. Further knowledge of these mechanisms will inform drug discovery, since GPCRs are promising therapeutic targets for cancer.

Inferring Differential Networks by Integrating Gene Expression Data With Additional Knowledge

“… If the gene is associated with prostate cancer (PCa) or enzalutamide-resistant (ER) according to literature search ( Wu et al, 2006 ; Tam et al, 2007 ; Lin et al, 2015 ; Wang et al, 2018 ; Handle et al, 2019 ; Chen et al, 2020 ; Kase et al, 2020 ; Balijepalli et al, 2021 ; Dickson et al, 2021 ; Furlan et al, 2021 ), a ○ is placed in the corresponding entry. The p -value of each gene is computed by Wilcoxon rank-sum test.…”

“…In this paper, based on gene expression data and additional biological knowledge, we propose a novel differential network estimation method named weighted joint sparse penalized D-trace model (WJSDM), to infer the changes of gene regulatory networks between two different states. By employing D-trace loss function and using a revised Kendall's tau correlation, our method can directly infer the differential network between two different states from gene expression data with missing (Wu et al, 2006;Tam et al, 2007;Lin et al, 2015;Wang et al, 2018;Handle et al, 2019;Chen et al, 2020;Kase et al, 2020;Balijepalli et al, 2021;Dickson et al, 2021;Furlan et al, 2021) values. Furthermore, to integrate the gene expression data collected from different data platforms and utilize the information provided by various prior biological knowledge, we propose a weighted group bridge penalty function, which enable our model to draw support from multiple related data sets.…”

Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth

“…The actions of LPA are mediated by six specific GPCRs, namely LPAR 1-6, and two unspecific GPCRs-the GPR87 and P2Y5 receptors. Specific LPA receptors are coupled to the G s , G i/o , G q/11 , and/or G 12/13 proteins [130]. Interestingly, it was observed that MCs express the LPAR1-5 gene [131].…”

Designing Dual Inhibitors of Autotaxin-LPAR GPCR Axis

“…LPA is generated either by hydrolysis of LPC by ATX or via the de novo pathway of glycerol 3-phosphate esterification by glycerol-3-phosphtae acyltransfarase-1 (GPAT-1). ATX, LPAR1 and LPAR2 are overexpressed in different tumor types, including ovarian cancer, osteocarcinoma, metastatic melanoma, neuroblastoma, breast cancer, pancreatic cancer, prostate cancer, and hepatocellular carcinoma [ 43 , 60 ]. Expression of ATX and/or LPAR can be further increased upon chemo- or radiotherapy, as shown for breast cancer [ 44 , 61 ].…”