Promising Pharmacological Directions in the World of Lysophosphatidic Acid Signaling

Abstract

Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named LPA1-LPA6. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models. To date, at least three compounds have passed phase I and phase II clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. This review focuses on the promising therapeutic directions emerging in LPA signaling toward ameliorating several diseases, including cancer, fibrosis, arthritis, hydrocephalus, and traumatic injury.

Diverse effects of LPA4, LPA5 and LPA6 on the activation of tumor progression in pancreatic cancer cells

“…Among LPA receptors, LPA 4 , LPA 5 and LPA 6 are structurally distance from other LPA receptors [1,2]. LPA 4 and LPA 5 induced neurite retraction and stress fiber formation in neural cells.…”

“…Lysophosphatidic acid (LPA) is an extracellular physiological mediator and interacts with G protein-coupled transmembrane LPA receptors (LPA receptor-1 (LPA 1 ) to LPA 6 ) [1,2]. LPA signaling via LPA receptors induces a variety of cellular functions, such as cell proliferation, differentiation, morphogenesis, cell motility and protection from apoptosis [1,2].…”

“…LPA signaling via LPA receptors induces a variety of cellular functions, such as cell proliferation, differentiation, morphogenesis, cell motility and protection from apoptosis [1,2]. In cancer cells, the individual LPA receptors exhibit the different responses, dependent on types of cells [3].…”

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

“…[4][5][6][7] Some promising studies are underway to access the therapeutic potential of ATX inhibitor and/or lysophosphatidate receptor (LPAR) antagonists. 8 Here, the authors review current studies, focusing on the impact of the ATX/LPA axis in pancreatic cancer and the potential use of targeting the ATX/LPA circuits on pancreatic cancer therapy.…”

Chitinase 3-like 1 expression by human (MG63) osteoblasts in response to lysophosphatidic acid and 1,25-dihydroxyvitamin D3

“…Indeed at the time of this particular study there were no published works reporting on YKL-40 expression in response to LPA/related analogues for any mammalian cell type. Given that LPA, like YKL-40, is implicated in tissue repair, remodelling and fibrosis [28][29][30] we sought to investigate if LPA 4 could stimulate human osteoblast YKL-40 expression and how 1,25D might influence this.…”