Receptors, Volume 3, Issue 4 (December 2024) – 9 articles

Background: Lysophosphatidic acid (LPA) receptor 3 (LPA₃) is involved in many physiological and pathophysiological actions of this bioactive lipid, particularly in cancer. The actions of LPA and oleoyl-methoxy glycerophosphothionate (OMPT) were compared in LPA₃-transfected HEK 293 cells. Methods: Receptor phosphorylation, ERK 1/2 activation, LPA₃-β-arrestin 2 interaction, and changes in intracellular calcium were analyzed. Results: Our data indicate that LPA and OMPT increased LPA₃ phosphorylation, OMPT being considerably more potent than LPA. OMPT was also more potent than LPA to activate ERK 1/2. In contrast, OMPT was less effective in increasing intracellular calcium than LPA. The LPA-induced LPA₃-β-arrestin 2 interaction was fast and robust, whereas that induced by OMPT was only detected at 60 min of incubation. LPA- and OMPT-induced receptor internalization was fast, but that induced by OMPT was more marked. LPA-induced internalization was blocked by Pitstop 2, whereas OMPT-induced receptor internalization was partially inhibited by Pitstop 2 and Filipin and entirely by the combination of both. When LPA-stimulated cells were rechallenged with 1 µM LPA, hardly any response was detected, i.e., a “refractory” state was induced. However, a conspicuous and robust response was observed if OMPT was used as the second stimulus. Conclusions: The differences in these agents’ actions suggest that OMPT is a biased agonist. These findings suggest that two binding sites for these agonists might exist in the LPA₃ receptor, one showing a very high affinity for OMPT and another likely shared by LPA and OMPT (structural analogs) with lower affinity. Full article

Background: Nitric oxide (NO) is a gaseous molecule considered to be a protagonist in the dilation of blood vessels, and its property and/or bioavailability are reduced in pathophysiological conditions such as cardiovascular diseases. Therefore, its exogenous administration becomes attractive, and new classes of compounds able to induce NO release have emerged to minimize the adverse effects found by existing NO donor drugs. Objective: Our aim was to investigate the vasorelaxant effect and mechanism of action induced by the ruthenium complex, which contains nitric oxide in its structure, [Ru(phen)₂(TU)NO](PF₆)₃ (FOR 911B), in isolated rat aorta. Methods: The animals were euthanized, and the aorta artery was identified, removed, and immediately placed in modified Krebs–Henseleit solution. To verify tissue viability, a contraction was obtained with phenylephrine (Phe) (0.1 μM), and to assess endothelial integrity, acetylcholine (ACh) (1 μM) was added. Results: In the present study, we demonstrated, for the first time, that FOR 911B promotes vasorelaxation in a concentration-dependent manner in isolated rat aortic artery rings. After the removal of the vascular endothelium, the potency and efficacy of the relaxation were not altered. With pre-incubation with hydroxocobalamin, the relaxing response was abolished, and with the use of ODQ, the main NO receptor blocker, the vasorelaxant effect was attenuated with a shift of the curve to the right. To investigate the participation of K⁺ channels, the solution concentration was changed to KCl (20 and 60 mM), and it was pre-incubated with the non-selective K⁺ channels blocker (TEA). Under these conditions, relaxation was altered, demonstrating that K⁺ channels are activated by FOR 911B. By selectively blocking the different subtypes of K⁺ channels with specific blockers, we demonstrated that the subtypes K_V, K_IR, SK_Ca, and BK_Ca are involved in the vasodilator effect induced by FOR 911B. Conclusions: The results obtained demonstrated that FOR 911B promotes vascular relaxation in aortic artery rings in a concentration-dependent manner and independent of the vascular endothelium through the participation of the NO/sGC/cGMP pathway, as well as with the involvement of different K⁺ channels. Full article

Work with novel indicators that report intracellular ATP concentrations with improved spatial and temporal resolution have challenged the current consensus that under physiological conditions, intracellular ATP concentrations are not rate-limiting to enzymatic reactions. Recent data from cardiac myocytes and cultured neurons show marked fluctuations of intracellular ATP levels, as well as evidence for compartmentalization. It is likely that the availability of these genetically encoded indicators will produce rapid progress in the mapping of the dynamics of intracellular ATP concentrations in various types of cells. Here, a brief account of the most recent indicators is provided as well as a review of how natural evolution appears to have obviated the potential shortage of the ATP supply to one of key enzymes of the cyclic AMP signaling cascade, adenylyl cyclase 9. Full article

Reactive oxygen species (ROS) encompass various molecular oxygen derivatives naturally produced during aerobic metabolism, including superoxide anions, hydrogen peroxide, and hydroxyl radicals. Excessive ROS production leads to oxidative distress, causing cellular damage and contributing to various pathologies, often alongside inflammation. Endogenous sources of ROS include mitochondrial activity and NADPH oxidases. The antioxidant system, comprising enzymes such as superoxide dismutase, peroxiredoxin, and catalase, mitigates ROS-induced damage. This review explores the regulation of ROS by membrane receptors, focusing on B1 and B2 kinin receptors and histamine H2 receptors, which are implicated in vasodilation, angiogenesis, inflammation, and gastric acid secretion. Understanding these interactions provides insights into ROS modulation and its role in disease mechanisms. Full article

Prostate cancer (PCa) is the most prevalent cancer among men globally. In addition to environmental risk factors, genetic factors play a crucial role in its development and progression, highlighting the regulation of key genes as an essential aspect. The androgen receptor gene (AR) plays a pivotal role in this disease, so its post-transcriptional regulation must be meticulously coordinated. In this review, we explore the role of microRNAs (miRNAs) in the regulation of AR in PCa, a field not yet fully investigated. We note that the AR, due to its extensive 3′UTR region, is targeted by numerous miRNAs, and that this regulation can occur at different levels: directly, indirectly, and through mutual regulation, thus amplifying the influence of these molecules on AR regulation. Full article

Amino acid transporters play pivotal roles in cancer biology, including in urological cancers. Among them, L-type amino acid transporter 1 (LAT1), alanine-serine-cysteine transporter 2 (ASCT2), and cystine-glutamate transporter (xCT) have garnered significant attention due to their involvement in various aspects of tumor progression and response to therapy. This review focuses on elucidating the regulation and functions of these amino acid transporters in urological cancers, including prostate, bladder, and renal cancers. Understanding the intricate regulatory mechanisms governing these amino acid transporters is essential for developing effective therapeutic strategies. Furthermore, exploring their interactions with signaling pathways and microenvironmental cues in the context of urological cancers may uncover novel therapeutic vulnerabilities. This comprehensive overview highlights the importance of amino acid transporters, particularly LAT1, ASCT2, and xCT, in urological cancers and underscores the potential of their inhibitors as therapeutic targets for improving patient outcomes. Full article

Folate receptor alpha (FRα) is a glycosylphosphatidylinositol (GPI) membrane-anchored protein containing three N-glycosylated residues at the N47, N139, and N179 termini. These glycosylation sites have been reported to be crucial for the receptor’s structural integrity and its ability to bind and internalize FA. Here, we investigated the role of FRα glycosylation in the binding and internalization efficacy of FA–DABA–SMA in pancreatic PANC-1 cancer cells. There is a strong association of the FA copolymer with FRα with a Pearson coefficient R-value of 0.7179. PANC-1 cancer cells were pretreated with maackia amurensis lectin II (MAL-2), sambucus Nigra lectin (SNA-1), peanut agglutinin (PNA), and wheat germ agglutinin lectin (WGA) at different doses followed by 20 kDa and 350 kDa FA–DABA–SMA loaded with coumarin 153 (C153). Increasing the dosage of MAL2, SNA-1, PNA, and WGA concomitantly and significantly increased the internalization of C153-loaded FA–DABA–SMA in the cells. The half maximal effective lectin concentrations (EC50) to induce cellular internalization into the cytoplasm of the lectins for MAL-2 were 35.88 µg/mL, 3.051 µg/mL for SNA-1, 7.883 µg/mL for PNA, and 0.898 µg/mL for WGA. Live cell imaging of the internalization of 20 kDa and 350 kDa FA copolymers indicated an aggregation of 350 kDa copolymer with FRα in the cytoplasm. In contrast, the 20 kDa FA copolymer remained in the membrane. The data indicate for the first time that the mobile positions of the glycosyl radical groups and the receptor tilt in generating steric hindrance impacted the individual FRα receptors in the binding and internalization of 350 kDa FA–DABA–SMA in cancer cells. Full article

This review focuses on the pivotal roles of nuclear receptors (NRs) in driving endocrine resistance in prostate and breast cancers. In prostate cancer (PCa), androgen receptor (AR) amplification, mutations, and altered coactivator interactions sustain tumor growth under androgen deprivation therapy (ADT), leading to castration-resistant prostate cancer (CRPC). Orphan NRs like RORβ, TLX, and COUP-TFII further contribute to CRPC by regulating stemness and therapeutic resistance mechanisms. In breast cancer, NRs, including estrogen receptor alpha (ERα), androgen receptor (AR), glucocorticoid receptor (GR), and liver receptor homolog-1 (LRH-1), modulate estrogen signaling pathways and alternative survival mechanisms like PI3K/AKT/mTOR and NFκB, promoting resistance to endocrine therapies such as tamoxifen. Understanding these NR-mediated mechanisms is critical for developing targeted therapies to overcome endocrine resistance and improve patient outcomes in hormone-dependent cancers. Full article

This review article explores the fundamental role of receptor targeting in overcoming drug resistance in cancer therapy, an area of critical concern given the persistently high rates of cancer morbidity and mortality globally. We highlight how receptor biology intersects with the development of therapeutic resistance with a specific focus on anti-angiogenic agents, immune checkpoint inhibitors, and monoclonal antibodies, which directly or indirectly influence receptor pathways. We also explore how other receptor tyrosine kinases can initially suppress tumor growth, yet often lead to resistance, underscoring the need for novel combinatorial approaches that incorporate advanced receptor modulation techniques. Further, the review delves into the mechanisms by which modulation of the tumor microenvironment and immune system via receptor pathways can overcome resistance to traditional immunotherapies. Additionally, emerging technologies in receptor-targeted nanomedicine are also highlighted, showcasing their potential to revolutionize drug delivery and improve therapeutic outcomes by targeting specific receptor interactions. Ultimately, this review calls for a deeper understanding of receptor dynamics to develop more precise interventions, including insights from various healthcare settings that can prevent or circumvent drug resistance, thus enhancing patient outcomes in oncology. Full article