Molecular mechanisms of target recognition by lipid GPCRs: relevance for cancer

Jaarsveld, Marijn T. M. van; Houthuijzen, Julia M.; Voest, Emile E.

doi:10.1038/onc.2015.467

Cited by 17 publications

(19 citation statements)

References 346 publications

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“…Limited information exists regarding the profile of GPCRs expressed by malignant cells. Prior studies primarily assessed individual GPCRs, in terms of expression, signaling and functional activities ( Lappano and Maggiolini, 2011 ; Feigin, 2013 ; O’Hayre et al, 2014 ; Bar-Shavit et al, 2016 ; Liu et al, 2016 ; Van Jaarsveld et al, 2016 ). TaqMan GPCR arrays provide an unbiased method to identify and quantify non-chemosensory GPCRs (other than those for taste, olfaction, and vision).…”

Section: Resultsmentioning

confidence: 99%

GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets

et al. 2018

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G protein-coupled receptors (GPCRs), the largest family of targets for approved drugs, are rarely targeted for cancer treatment, except for certain endocrine and hormone-responsive tumors. Limited knowledge regarding GPCR expression in cancer cells likely has contributed to this lack of use of GPCR-targeted drugs as cancer therapeutics. We thus undertook GPCRomic studies to define the expression of endoGPCRs (which respond to endogenous molecules such as hormones, neurotransmitters and metabolites) in multiple types of cancer cells. Using TaqMan qPCR arrays to quantify the mRNA expression of ∼340 such GPCRs, we found that human chronic lymphocytic leukemia (CLL) cells/stromal cells associated with CLL, breast cancer cell lines, colon cancer cell lines, pancreatic ductal adenocarcinoma (PDAC) cells, cancer associated fibroblasts (CAFs), and PDAC tumors express 50 to >100 GPCRs, including many orphan GPCRs (which lack known physiologic agonists). Limited prior data exist regarding the expression or function of most of the highly expressed GPCRs in these cancer cells and tumors. Independent results from public cancer gene expression databases confirm the expression of such GPCRs. We propose that highly expressed GPCRs in cancer cells (for example, GPRC5A in PDAC and colon cancer cells and GPR68 in PDAC CAFs) may contribute to the malignant phenotype, serve as biomarkers and/or may be novel therapeutic targets for the treatment of cancer.

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Section: Resultsmentioning

confidence: 99%

GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets

et al. 2018

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“…The serum metabolomic profile of men with tumors extending through the prostatic capsule (i.e., T3) was characterized by reduced signal for several glycerophospholipids, primary bile acid lipids and greater signal for sphingomyelins. The inositol, choline and ethanolamine glycerophospholipids are key cell membrane structural and signaling compounds that provide biosynthetic support during rapid cell proliferation [ 19 , 20 ]. Sphingomyelins are a primary component in membrane vesicles shed from actively growing prostate and other malignant cells that may facilitate tumor cell invasion and escape from immune surveillance [ 21 – 24 ], and they have been found to be significantly higher in cancer patients than in non-cases [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Prospective serum metabolomic profile of prostate cancer by size and extent of primary tumor

et al. 2017

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Two recent investigations found serum lipid and energy metabolites related to aggressive prostate cancer up to 20 years prior to diagnosis. To elucidate whether those metabolomic profiles represent etiologic or tumor biomarker signals, we prospectively examined serum metabolites of prostate cancer cases by size and extent of primary tumors in a nested case-control analysis in the ATBC Study cohort that compared cases diagnosed with T2 (n = 71), T3 (n = 51), or T4 (n = 15) disease to controls (n = 200). Time from fasting serum collection to diagnosis averaged 10 years (range 1–20). LC/MS-GC/MS identified 625 known compounds, and logistic regression estimated odds ratios (ORs) associated with one-standard deviation differences in log-metabolites. N-acetyl-3-methylhistidine, 3-methylhistidine and 2′-deoxyuridine were elevated in men with T2 cancers compared to controls (ORs = 1.38–1.79; 0.0002 ≤ p ≤ 0.01). By contrast, four lipid metabolites were inversely associated with T3 tumors: oleoyl-linoleoyl-glycerophosphoinositol (GPI), palmitoyl-linoleoyl-GPI, cholate, and inositol 1-phosphate (ORs = 0.49–0.60; 0.000017 ≤ p ≤ 0.003). Secondary bile acid lipids, sex steroids and caffeine-related xanthine metabolites were elevated, while two Krebs cycle metabolites were decreased, in men diagnosed with T4 cancers. Men with T2, T3, and T4 prostate cancer primaries exhibit qualitatively different metabolite profiles years in advance of diagnosis that may represent etiologic factors, molecular patterns reflective of distinct primary tumors, or a combination of both.

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“…The mechanisms of lipid signal transduction are poorly understood, but often involve GPCRs. As reviewed recently (96), over 50 GPCRs have been implicated in signaling lipids that include lysophospholipids, phospholipids, fatty acids, and eicosanoids. Dysregulation of these lipid GPCRs contribute to diverse cancer-related processes and may be therapeutically exploited (96).…”

Section: Lipid Messengers Bind To Receptors and Target Proteins As Ormentioning

confidence: 99%

Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

Manna

Nieminen

Vattulainen

2019

Annu. Rev. Biophys.

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Cell signaling controls essentially all cellular processes. While it is often assumed that proteins are the key architects coordinating cell signaling, recent studies have shown more and more clearly that lipids are also involved in signaling processes in a number of ways. Lipids do, for instance, act as messengers, modulate membrane receptor conformation and dynamics, and control membrane receptor partitioning. Further, through structural modifications such as oxidation, the functions of lipids as part of signaling processes can be modified. In this context, in this article we discuss the understanding recently revealed by atomistic and coarse-grained computer simulations of nanoscale processes and underlying physicochemical principles related to lipids’ functions in cellular signaling.

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Molecular mechanisms of target recognition by lipid GPCRs: relevance for cancer

Cited by 17 publications

References 346 publications

GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets

GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets

Prospective serum metabolomic profile of prostate cancer by size and extent of primary tumor

Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

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