Deregulation of lysophosphatidic acid metabolism in oral cancer promotes cell migration via the up-regulation of COX-2

Abstract

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and accounts for 300,000 new cases yearly. The five-year survival rate is approximately 50% and the major challenges to improving patient prognosis include late presentation, treatment resistance, second primary tumours and the lack of targeted therapies. Therefore, there is a compelling need to develop novel therapeutic strategies. In this study, we have examined the effect of lysophosphatidic acid (LPA) on OSCC cell migration, invasion and response to radiation, and investigated the contribution of cyclooxygenase-2 (COX-2) in mediating the tumour promoting effects of LPA. Using the TCGA data set, we show that the expression of the lipid phosphate phosphatases (LPP), LPP1 and LPP3, was significantly down-regulated in OSCC tissues. There was no significant difference in the expression of the ENPP2 gene, which encodes for the enzyme autotaxin (ATX) that produces LPA, between OSCCs and control tissues but ENPP2 levels were elevated in a subgroup of OSCCs. To explore the phenotypic effects of LPA, we treated OSCC cell lines with LPA and showed that the lipid enhanced migration and invasion as well as suppressed the response of the cells to irradiation. We also show that LPA increased COX-2 mRNA and protein levels in OSCC cell lines and inhibition of COX-2 activity with the COX-2 inhibitor, NS398, attenuated LPA-induced OSCC cell migration. Collectively, our data show for the first time that COX-2 mediates some of the pro-tumorigenic effects of LPA in OSCC and identifies the ATX-LPP-LPA-COX-2 pathway as a potential therapeutic target for this disease.

E2F7 drives autotaxin/Enpp2 transcription via chromosome looping: Repression by p53 in murine but not in human carcinomas

“…ATX expression is amplified in various human carcinomas as well as in different cell types of the TME. [2][3][4][5] Our initial observation that p53-KO mice have elevated Enpp2 expression prompted us to investigate if p53 can regulate the transcription of Enpp2 expression. 40 In the present study, we showed that MEF derived from p53-KO or p53 R172H mice indeed express more ATX than MEF derived from WT mice, suggesting that WT p53 represses Enpp2 transcription.…”

“…ATX expression is amplified in various human carcinomas as well as in different cell types of the TME 2–5 . Our initial observation that p53‐KO mice have elevated Enpp2 expression prompted us to investigate if p53 can regulate the transcription of Enpp2 expression 40 .…”

“…LPA functions through activation of multiple targets including LPA GPCR (LPAR). 1 ATX is elevated in many types of carcinomas [2][3][4][5] and drives cancer progression by promoting invasion, angiogenesis, metastasis, therapy resistance, and inhibits tumor immunity. [6][7][8][9] ATX/LPA is also secreted by cells of the tumor microenvironment (TME) [10][11][12] and regulates the communication between cancer cells and their TME.…”

The Emerging Role of LPA as an Oncometabolite

“…PI3K/AKT signalling seems to be at the epicentre of LPA pro-tumourigenic actions, as it has also been suggested to drive LPA-induced proliferation and migration in oesophageal squamous cell carcinoma [103]. LPP1/3 expression is downregulated in oral cancer, whereas ATX displays high expression, and ATX-synthesised LPA subsequently induces cyclooxygenase-2 (COX-2) mRNA expression to promote cell migration [104].…”

Design and Development of Autotaxin Inhibitors

“…We have mentioned the idea of treating of related diseases by blocking ATX-LPA axis above. Recently, many studies have shown that inhibiting ATX can have a promising therapeutic effect on many diseases, such as the growth and metastasis of various tumors such as oral squamous cell carcinoma (OSCC) [31] and breast cancer [32], peritoneal spread in patients with pancreatic ductal adenocarcinoma (PDAC) [33], cardiovascular disease [34], fibrosis of organs such as kidney, heart and lung [35,36], and central nervous system disease [37,38]. It has been shown that ATX is essential for the development of embryos.…”