Abstract
Lysophosphatidic acid (LPA) is a bioactive lipid mediator primarily derived from membrane phospholipids. LPA initiates cellular effects upon binding to a family of G protein-coupled receptors, termed LPA receptors (LPAR1 to LPAR6). LPA signaling drives cell migration and proliferation, cytokine production, thrombosis, fibrosis, angiogenesis, and lymphangiogenesis. Since the expression and function of LPA receptors are critical for cellular effects, selective antagonists may represent a potential treatment for a broad range of illnesses, such as cardiovascular diseases, idiopathic pulmonary fibrosis, voiding dysfunctions, and various types of cancers. More new LPA receptor antagonists have shown their therapeutic potentials, although most are still in the preclinical trial stage. This review provided integrative information and summarized preclinical findings and recent clinical trials of different LPA receptor antagonists in cancer progression and resistance. Targeting LPA receptors can have potential applications in clinical patients with various diseases, including cancer.
Highlights
Lysophosphatidic acid (LPA) and LPA receptors (LPARs), including LPAR1 to LPAR6, are integral parts of signaling pathways involved in cellular proliferation/migration/ survival, vascular homeostasis, stromal remodeling, lymphocytes trafficking, and immune regulation [1,2,3]
Apart from cancer, LPAR1 antagonists, BMS-986020, and BMS-986278 focused on idiopathic pulmonary fibrosis (IPF) and aimed to prove the application of LPAR
Despite the apparent relevance of LPA signaling in cancer initiation, progression, metastasis, and developments of resistance against chemo- and radio-induced cancer cell death, no inhibitors targeting LPARs have progressed to cancer-related clinical trials far
Summary
Lysophosphatidic acid (LPA) and LPA receptors (LPARs), including LPAR1 to LPAR6, are integral parts of signaling pathways involved in cellular proliferation/migration/ survival, vascular homeostasis, stromal remodeling, lymphocytes trafficking, and immune regulation [1,2,3]. Aberrant ATX-LPA-LPAR axis may be involved in the development and progression of many pathologic conditions such as cancer and metastasis [6,7], radio- and chemo-resistances [8,9,10,11,12], fibrotic diseases [13], neuropathic pain [14], arthritis [15], metabolic syndromes [16], and atherosclerosis [17]. Understanding ATX/LPA expression and LPAR-mediated signals elucidated our understanding of the disease mechanisms and highlighted the therapeutic potential of the druggable ATXLPAR axis. Enormous in vivo and in vitro investigations have demonstrated pharmacological antagonization of LPAR to be of paramount significance in reversing pathologic responses. This article sought to update current progress regarding LPAR. PgAlycisercooln3v-eprhtoedspthoaLteP(AG3thPr)oounghthPeLmAi1toacnhdonPdLrAia2g. eOnenrthaeteodtihnetrahcaenlldu,lamr LoPnAoavciyalgalcyyclegrloylce(rMolAkGin)aasne d(AgGlyKc)earnold3g-lpyhceorsopphhaotesp(hGa3tPe)acoynlttrhaensmfeirtaosceh(oGnPdAriTa), greensepreactteidveilnyt.racellular LPA via acylglycerol kinase (AGK) and glycerophosphate acyltransferase (GPAT), respectively
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