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    • br Involvement of LPA receptors in

    2023-03-22


    Involvement of LPA receptors in cancer LPA׳s effects are mediated by at least six different G protein-coupled receptors (LPA1–6). Human gastric and ovarian cancers overexpress the mRNA encoding LPA1 and LPA2 compared to healthy tissues [6], [11], [12]. Papillary and follicular thyroid cancers exhibit aberrant expression of LPA2[13] as well as breast cancers where its expression is significantly increased compared to that of normal mammary glands [14]. It has also been reported that colorectal cancers exhibit decreased expression in LPA1, increased in LPA2, while LPA3 levels were not affected [15]. Few studies have reported the involvement of the receptors LPA4, LPA5 and LPA6 in cancers. Intriguingly, LPA6 (P2Y5) is so far the sole LPA receptor whose mutation is responsible for a human disease, as found in cases of Pakistani and Turkish families with autosomal recessive hypotrichosis [16], [17], and was also found to be associated with hereditary Marimastat receptor tumors [18]. The P2Y5 gene (P2RY5) is located within the tumor suppressor retinoblastoma RB1 (intron 17) in a reverse orientation [19]. In bladder cancer, loss of the RB1 segment containing P2RY5 is associated with neoplastic expansion [18], [19]. Nucleotide substitutions in P2RY5 represent a risk factor that predispose cancer, especially when combined with smoking. The introduction of P2RY5 in bladder cancer cells where it is not originally expressed leads to cell cycle arrest and apoptosis of tumor cells [18], [19]. Furthermore, it was shown that families with hereditary risk of breast, colon, lung, prostate or uterus cancers carry a germline mutation in the P2RY5 gene [18]. Therefore, this gene may be considered as a tumor suppressor gene.
    Functional implications of LPA in cancer cell proliferation and motility LPA receptors share intracellular signaling pathways dependent on Gα (LPA1–4 and LPA6), Gα12/13 (LPA1-2, LPA4–6), Gα (LPA1–5) and Gα (LPA4 and LPA6). Therefore, LPA receptors can have potentially redundant or opposite effects on cell biology. Most eukaryotic cells express numerous LPA receptors. Since the publication of works from Hama and colleagues, LPA1 is now considered responsible for the motility activity of LPA [20]. Shida and collaborators also showed that LPA stimulates the proliferation, migration and adhesion of LPA1 overexpressing colon cancer cells while it stimulates the proliferation but not the migration and adhesion of cells expressing high levels of LPA2[12]. Such observations were also found in human colorectal cancer cells [21]. Our lab showed that blocking LPA1 activity inhibits breast cancer cell migration and proliferation [22], [23]. However, LPA-induced migration might not only be devoted to LPA1 as LPA3 was reported to control migration and invasion of liver cancer cells [24]. Furthermore, silencing of LPA2 or LPA3 expression using lentivirus-coding siRNAs inhibited the migration and invasion of ovarian cancer cells [24]. Degrading basal membrane matrix is required for tumor cells to invade and colonize targeted tissues. Matrix metalloproteinases (MMPs) are proteolytic enzymes that play key roles in tumor invasion and metastasis. LPA up-regulates MMP-dependent proMMP-2 activation in ovarian cancer cells leading to enhanced pericellular MMP activity [25]. Invasion of LPA-treated ovarian cancer cells was mediated through MMP-9 production via a Ras/Rho/ROCK-dependent mechanism [26]. LPA1 controls MMP-9 secretion that induces the invasion of human hepatocellular carcinoma cells [27]. Other LPA receptors might also regulate the secretion of other MPPs such as MMP-7 via LPA2 in ovarian cancer cells [28]. Using B16 cells as a model for melanoma, the group of W. Moolenaar showed that LPA and serum almost completely inhibit the transwell B16 cell migration [29]. This anti-migratory response to LPA was dependent on the cAMP level and protein kinase A (PKA) activity. The study further demonstrated that the LPA-induced chemorepulsion was mediated specifically by LPA5 and determined that alkyl-LPA(18:1) was 10-fold more potent than acyl-LPA(18:1) on B16 cell-inhibited migration [29]. This work raised two important points that might be taken into account when addressing LPA biological functions. First, because pleiotropic activities of LPA are likely the consequence of co-activation signals induced by multiple receptors, the complete screening and levels of expression of LPA receptors have to be determined before analyzing LPA׳s functions. Second, LPA exists in multiple forms due to high variability of its fatty acid chain moiety. Therefore, cells with the same pattern of LPA receptor expression could potentially behave differently depending on the physiopathological context in response to different sub-types of LPA. Such considerations deserve attention when interpreting in vitro studies because they are predominantly carried out using 1-acyl-LPA(18:1).