Targeting Lysophosphatidic Acid in Cancer: The Issues in Moving from Bench to Bedside

Xu, Yan

doi:10.3390/cancers11101523

Cited by 40 publications

(37 citation statements)

References 284 publications

(444 reference statements)

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“…Given the role of LPA and LPA receptors in tumor biology, the effective targeting of these receptors has become an important goal in tumor research. This work has largely focused on approaches to reduce LPA synthesis, block LPA metabolic pathway activation, inhibit LPA receptor activity, and block signal transduction in the relevant pathways 266 . For example, the LPA3 receptor antagonist ki16425 has been reported to inhibit the migration and invasion of pancreatic cancer cells 267 .…”

Section: Therapeutic Strategies Targeting Lipid Metabolism Reprogrammmentioning

confidence: 99%

Lipid metabolism in cancer progression and therapeutic strategies

Zou

Shen

et al. 2020

MedComm

181

113

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Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune‐associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.

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Section: Therapeutic Strategies Targeting Lipid Metabolism Reprogrammmentioning

confidence: 99%

Lipid metabolism in cancer progression and therapeutic strategies

Zou

Shen

et al. 2020

MedComm

181

113

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“…To illustrate the whole mechanism visually, we constructed a diagram (shown as the Graphical Abstract) based on what we discovered in this study to illustrate the cell signaling pathways by which LPA induced RON expression in bladder cancer T24 cells. Since LPA was established as a target for cancer and the concept of targeting LPA needed to be moved to clinical cancer treatment [18], our present findings provided experimental evidence that could be helpful for developing new therapeutic strategies for bladder cancer therapy targeting LPA. Based on what we have found in this study, that LPA increased RON expression in an LPA receptor dependent manner, suppressing the LPA level or blocking LPA and the LPA receptor would be effective ways to suppress RON expression and, in turn, inhibit cell invasion.…”

Section: Discussionmentioning

confidence: 74%

“…More interestingly, LPA abnormalities are also involved in tumor progression [16] and autoimmune diseases [17]. LPAs have been known to play a role in a series of tumor development, including stimulation of proliferation, resisting cell death, and evading tumor suppressors by regulating the apoptotic pathways, inducing angiogenesis via upregulation of proangiogenic factors, enabling immortality and activating cell invasion [18]. LPA presumably acts through specific G-protein coupled receptors and is a potent inducer of cell survival, proliferation, and migration.…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid Upregulates Recepteur D’origine Nantais Expression and Cell Invasion via Egr-1, AP-1, and NF-κB Signaling in Bladder Carcinoma Cells

Khoi

Thuan

et al. 2020

IJMS

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Muscle invasive bladder carcinoma is a highly malignant cancer with a high mortality rate, due to its tendency to metastasize. The tyrosine kinase recepteur d’origine nantais (RON) promotes bladder carcinoma metastasis. Lysophosphatidic acid (LPA) is a phospholipid derivative, which acts as a signaling molecule to activate three high affinity G-protein coupled receptors, LPA1, LPA2, and LPA3. This in turn leads to cell proliferation and contributes to oncogenesis. However, little is known about the effects of LPA on invasive bladder cancer (IBC). In this study, we discovered that LPA upregulated RON expression, which in turn promoted cell invasion in bladder cancer T24 cells. As expected, we found that the LPA receptor was essential for the LPA induced increase in RON expression. More interestingly, we discovered that LPA induced RON expression via the MAPK (ERK1/2, JNK1/2), Egr-1, AP-1, and NF-κB signaling axes. These results provide experimental evidence and novel insights regarding bladder malignancy metastasis, which could be helpful for developing new therapeutic strategies for IBC treatment.

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“…Its downregulation sensitizes osteosarcoma cells to apoptosis with significant upregulation of ERS markers, GRP78, XBP1, and p-eIF2 α /CHOP, and inhibition of the PI3K/AKT/NF- κ B signaling axis [ 68 ]. Another member of the same family, lysophosphatidic acid receptor (LPAR), is known to regulate a variety of tumorigenic functions including proliferation, survival, angiogenesis, invasion, and metastasis [ 69 ] and is implicated in inhibiting ER stress-mediated apoptosis in mesenchymal cells by inhibition of p38 activation via the LPA1/3-Gi/ERK1/2/MAPK1 signaling axis under the conditions of hypoxia and serum deprivation [ 70 ]. The ERS-mediated protective effect was also observed in oligodendrocyte precursor cells upon induction of LPA1/3 receptors via modulation of UPR proteins BIP, GRP94, CHOP, and XBP1s [ 71 ].…”

Section: Ers In Cancermentioning

confidence: 99%

Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

Kumari

Reabroi

North

2021

Mediators of Inflammation

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G protein-coupled receptors (GPCRs) represent a large family of transmembrane proteins that transduce an external stimulus into a variety of cellular responses. They play a critical role in various pathological conditions in humans, including cancer, by regulating a number of key processes involved in tumor formation and progression. The epithelial-mesenchymal transition (EMT) is a fundamental process in promoting cancer cell invasion and tumor dissemination leading to metastasis, an often intractable state of the disease. Uncontrolled proliferation and persistent metabolism of cancer cells also induce oxidative stress, hypoxia, and depletion of growth factors and nutrients. These disturbances lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and induce a cellular condition called ER stress (ERS) which is counteracted by activation of the unfolded protein response (UPR). Many GPCRs modulate ERS and UPR signaling via ERS sensors, IRE1α, PERK, and ATF6, to support cancer cell survival and inhibit cell death. By regulating downstream signaling pathways such as NF-κB, MAPK/ERK, PI3K/AKT, TGF-β, and Wnt/β-catenin, GPCRs also upregulate mesenchymal transcription factors including Snail, ZEB, and Twist superfamilies which regulate cell polarity, cytoskeleton remodeling, migration, and invasion. Likewise, ERS-induced UPR upregulates gene transcription and expression of proteins related to EMT enhancing tumor aggressiveness. Though GPCRs are attractive therapeutic targets in cancer biology, much less is known about their roles in regulating ERS and EMT. Here, we will discuss the interplay in GPCR-ERS linked to the EMT process of cancer cells, with a particular focus on oncogenes and molecular signaling pathways.

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Targeting Lysophosphatidic Acid in Cancer: The Issues in Moving from Bench to Bedside

Cited by 40 publications

References 284 publications

Lipid metabolism in cancer progression and therapeutic strategies

Lipid metabolism in cancer progression and therapeutic strategies

Lysophosphatidic Acid Upregulates Recepteur D’origine Nantais Expression and Cell Invasion via Egr-1, AP-1, and NF-κB Signaling in Bladder Carcinoma Cells

Unraveling the Molecular Nexus between GPCRs, ERS, and EMT

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