ATX‑LPA axis facilitates estrogen‑induced endometrial cancer cell proliferation via MAPK/ERK signaling pathway

Abstract

Autotaxin (ATX) is a key enzyme that converts lysophosphatidylcholine to lysophosphatidic acid (LPA). ATX is a crucial factor that facilitates cancer progression; however, the effect of ATX on endometrial cancer has not been explored. The aim of the present study was to investigate the role of ATX in the progression of endometrial cancer. The immunohistochemical results revealed higher protein expression levels of ATX and LPA receptors (LPA 1, 2 and 3) in human endometrial cancer tissue than in non-carcinoma tissue. In addition, reverse transcription-quantitative polymerase chain reaction and western blotting analysis demonstrated that ATX and LPA receptor mRNA and protein expression was greater in Ishikawa cells, which are positive for estrogen receptor (ER), than in Hec-1A cells that exhibit low ER expression. Short interfering RNA knockdown of ATX in Ishikawa cells led to decreased cell proliferation and cell colony number, as determined by Cell Counting kit-8 and colony formation assays. Estrogen stimulated ATX mRNA expression. Inhibition of ATX decreased estrogen and LPA-induced cell proliferation. High LPA levels markedly elevated the phosphorylation levels of extracellular signal-regulated kinase (ERK). ATX downregulation moderately decreased estrogen- and LPA-induced phosphorylation of ERK. In addition, the ERK inhibitor, PD98059, reduced cell proliferation with estrogen, ATX and LPA treatment. The present study suggested that the ATX-LPA axis may facilitate estrogen-induced cell proliferation in endometrial cancer via the mitogen-activated protein kinase/ERK signaling pathway. The present study may provide ideas and an experimental basis for clinicians to identify new molecular targeted drugs for the treatment of endometrial cancer.

Lipid Phosphate Phosphatases and Cancer

“…Cancer cells express high levels of LPAR1–3 [ 61 ], which are GPCRs. LPAR1–3 couple to G proteins: Gi/o, Gq/11, and G12/13 [ 61 ], and activate PI3K (phosphoinositide 3-kinase) /AKT [ 114 , 115 ], PLC (phospholipase C) [ 116 ], and Rho pathways [ 116 ]. LPAR1–3 are elevated in brain [ 117 , 118 ], pancreatic [ 119 , 120 , 121 ], colon [ 122 , 123 ], and breast cancer [ 124 ], which is associated with enhanced tumor growth and metastasis.…”

C-reactive Protein as a Diagnostic and Prognostic Factor of Endometrial Cancer

“…It is also worth mentioning the fact that increased CRP levels and increased endometrial cancer risk are strongly associated with obesity and fat tissue is hormonally active [49]. Moreover, adipose tissue through estrogen and leptin promotes AKT/STAT3 and MAPK/ERK pathways and therefore these hormones could be as important or even more important in carcinogenesis and cancer progression than CRP and their role in endometrial cancer development and progression need an investigation [49][50][51]. Furthermore, natural or surgical fat loss decreases levels of CRP, leptin and estrogen, therefore, could be consider as prophylaxis and adjuvant treatment of endometrial cancer [52].…”

A Novel Therapeutic Reagent, KA-1002 for Alleviating Lysophosphatidic Acid-Mediated Inflammation Related Gene Expression in Swine Macrophages

“…In the previous report [27,28], downstream of LPA receptor activation, MAPK/ERK signaling pathway can be activated by LPA. In our study, we found that LPA treatment on swine macrophages strongly induced biological pathway for "role of MAPK signaling in the pathogenesis of influenza" and its related genes to be differentially regulated (Figure 3).…”