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  • In a follow up study the same research group further

    2021-09-08

    In a follow up study, the same research group further characterized FFA4 involvement in DU145 and PC-3 cancer cell lines by demonstrating that the anti-proliferative and anti-migration activities of FFA4 require the presence Tankyrase Inhibitors 22 of LPA1 receptor (LPA1R), suggesting a mechanism consistent with negative cross-talk [44]. Specifically, while agonism of FFA4 by EPA and TUG-891 inhibited proliferation and migration induced by both LPA and EGF in DU145 and PC-3 cells, siRNA knockdown of LPA1R abrogated the effects of the FFA receptor [44]. The effects of EPA and TUG-891 on epidermal growth-factor receptor (EGFR) signaling were also lost upon knockdown of the LPA1R, suggestive of mechanistic cross-talk within a triad between FFA4, LPA1R, and EGFR; whereby agonism of FFA4 directly inhibits LPA1R and as a consequence, inhibits LPA1R transactivation of EGFR (Fig. 1). Interestingly, knockdown of β-arrestin-2 completely abrogated LPA- and EGF- induced proliferation and migration in both DU145 and PC-3 cells, but this result also confounds the ability to study the specific role of FFA4/β-arrestin-2 axis in LPA- and EGF-mediated proliferation and migration [44]. While this study identified LPA1R as a critical intermediary of FFA4 effects, the direct mechanisms that modulate the FFA4-LPA1R cross-talk in prostate cancer Tankyrase Inhibitors 22 remain elusive, albeit, several putative pathways were speculated upon. First, since FFA4 is well known to recruit and interact with β-arrestin-2 [24], [25], [26], its agonism may sequester the scaffolding protein away from LPA1R, thereby inhibiting its ability to modulate LPA1R signals (Fig. 1). This effect would be similar to that seen in macrophages, where β-arrestin-2 recruitment subsequent to FFA4 agonism sequesters TAB1, inhibiting its downstream interactions with TAK1 and activation of the NF-κB nucleocomplex [24], [45]. Second, since agonism of FFA4 has been shown to rapidly activate PKC activity and the receptor itself is a substrate for PKC [36], it may be feasible that PKC activity that is induced upon FFA4 agonism facilitates direct heterologous phosphorylation of LPA1R, desensitizing its ability to signal further (Fig. 1). Finally, since LPA1R has been shown to form homo- and hetero- dimers with itself and other GPCRs [46], it is conceivable that agonist-induced heterodimerization of FFA4 with LPA1R may facilitate alterations to the signal capabilities of the latter receptor (Fig. 1). More research will be needed to decidedly determine the particular intracellular mechanism of action that FFA4 imparts to modulate activities of these two critical prostate mitogenic receptors. Furthermore, a specific role of FFA4 in androgen-dependent prostate cancers has not been examined and there is a lack of information on how the receptor may influence testosterone (T), its conversion by 5-α-reductase to dihydrotestosterone (DHT), the androgen receptor (AR), or downstream effects of AR on androgen response elements and transcriptional activity in these prostate cancers.
    Colorectal cancer cell lines and human CRC tissue Numerous studies have suggested that omega-3 PUFAs, particularly DHA and EPA, can slow the growth of colorectal cancers (CRC) and potentiate the sensitivity to anticancer agents [47], [48], [49], [50]. However, the evidence pointing to the mechanistic role of FFA4 in modulation of these effects has to date, been conflicting. Wu and colleagues found that FFA4 expression is highly upregulated in human CRC tissue compared to adjacent non-cancerous tissue, while there was no evidence in this report for expression of FFA1 [51]. Immunohistochemical analysis of 90 patient sample tissues of malignant CRC with surrounding nonmalignant tissue revealed elevated FFA4 expression in 65 of 90 patient samples, whereas 90 normal tissue samples contained low FFA4 expression, yielding a statistically significant increase of FFA4 expression in CRC tissues with p < 0.001 [51]. Moreover, there was a strong clinicopathologic correlation linked to FFA4 expression in human CRC tissues and the expression of the receptor was noted to increase as the clinical stage of cancer advanced, with 100% of stage III histological grade CRCs expressing high levels of FFA4. Additionally, tumor-lymph node-metastasis (TNM) staging demonstrated a positive correlation with high levels of FFA4 expression in 35 out of 40 metastases (p = 0.004) [51]. Finally, there was a significant correlation found between human CRC FFA4 expression and body weight, consistent with previous results associating FFA4 expression and obesity [52].