Lysophosphatidic acid receptor 4 signaling potentially modulates malignant behavior in human head and neck squamous cell carcinoma cells

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer worldwide. Despite improvement in therapeutic strategies, the prognosis of advanced HNSCC remains poor. The extacellular lipid mediators known as lysophosphatidic acids (LPAs) have been implicated in tumorigenesis of HNSCC. LPAs activate G-protein-coupled receptors not only in the endothelial differentiation gene (Edg) family (LPA1, LPA2, LPA3) but also in the phylogenetically distant non-Edg family (LPA4, LPA5, LPA6). The distinct roles of these receptor isoforms in HNSCC tumorigenesis have not been clarified. In the present study, we investigated the effect of ectopic expression of LPA4 in SQ-20B, an HNSCC cell line, expressing a trivial level of endogenous LPA4. LPA (18:1) stimulated proliferation of SQ-20B cells, but did not affect proliferation of HEp-2, an SCC cell line expressing higher levels of LPA4, comparable to those of with LPA1. LPA-stimulated proliferation of SQ-20B cells was attenuated by Ki16425 and Rac1 inhibitor, but not by Y-27632. Infection with doxycycline-regulatable adenovirus vector expressing green fluorescent protein-tagged LPA4 (AdvLPA4G) abolished LPA-stimulated proliferation in SQ-20B cells with the accumulation of G2/M-phasic cells. Ectopic LPA4 induction further downregulated proliferation of Ki16425-treated SQ-20B cells, of which downregulation was partially recovered by LPA. Ectopic LPA4 induction also downregulated proliferation of Rac1 inhibitor-treated SQ-20B cells, however, LPA no longer recovered it. Finally, LPA-induced cell motility was suppressed by ectopic LPA4 expression as well as by Ki16425, Rac1 inhibitor or Y-27632. Our data suggest that LPA4 signaling potentially modulates malignant behavior of SQ-20B cells. LPA signaling, which is mediated by both Edg and non-Edg receptors, may be a determinant of malignant behavior of HNSCC and could therefore be a promising therapeutic target.

Retracted: Microrna‐139‐5p inhibits epithelial‐mesenchymal transition and fibrosis in post‐menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway

“…Besides, LPA, present in serum, ascites and urine, was reported to be correlated with cell proliferation and invasion in cancers including bladder cancer and LPA receptor, a G‐protein coupled receptor, which was regarded as a promising therapeutic target for malignant cancers . For example, LPAR4 was a potential regulator of malignant behavior in head and neck squamous cell carcinoma cells and a potential therapeutic target . LPA also played a crucial role in various biological processes such as inflammation and uterine remodeling .…”

“…10,11 LPAs are ubiquitous bioactive molecules modulating different cellular events including proliferation, migration, and anti-apoptotic reaction in diversified types of cells, which are thus largely involved in development, homeostatic regulations and disease processes. 12 LPA receptor 4 (LPAR4), located on chromosome Xq21.1 and D-region of chromosome X in mouse, is observed in the skin, brain, thymus, heart, lung and uterus. 13 It has also been revealed that LPARs are associated with fibrosis in kidney, lung and liver.…”

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

“…In contrast to motility-stimulation of LPAR, Lee et al 45 provided genetic and biochemical evidences that LPAR4 was a suppressor of LPA-dependent cell migration and invasion; they found that LPAR4 attenuated LPAR1-driven migration and invasion, indicating functional antagonism between two subtypes of LPAR. Similarly, Matayoshi et al 88 found that LPAR4 negatively modulated the malignant behavior of head and neck squamous cell carcinoma cells. A study in pancreatic cancer shows that LPAR 4, 5, 6 have the diverse effects on the activation of tumor progression; they demonstrated that LPAR4 and LPAR5 negatively and LPAR6 positively regulated the malignant properties in pancreatic cancer cells.…”

Transactivation of epidermal growth factor receptor through platelet-activating factor/receptor in ovarian cancer cells

“…PGE2 has been reported to activate the EGFR in hepatocarcinoma [25]. EGFR activation in response to GPCR ligands, including lysophosphatidic acid (LPA), has been reported in HNSCC cells [26]. Thus, the combined inhibition of EGFR and GPCR might enhance antitumor effects compared with single agents targeting EGFR alone.…”