Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment

Xu, Yan

doi:10.3390/cancers10070227

Cited by 39 publications

(38 citation statements)

References 171 publications

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“…In particular, SphK2 has shown potent anti-inflammatory effects by regulating macrophage activation and polarization (Ji et al, 2019 ; Weigert et al, 2019 ). Moreover, the cellular localization of the SphKs was shown to be associated with epithelial ovarian cancer (Xu, 2018 ), Sandhoff disease (Wu et al, 2008 ), and Alzheimer’s disease (Dominguez et al, 2018 ). Based on the fact that the anti-MS action of FTY720 is catalyzed by SphK2 as mentioned above (Fischer et al, 2011 ), it is reasonable to suggest that SphK2 has neuroprotective functions in MS and EAE.…”

Section: Discussionmentioning

confidence: 99%

Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model

Chen

Cao

Luo

et al. 2020

Front. Mol. Neurosci.

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Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS) that currently does not have any effective treatment. Experimental autoimmune encephalomyelitis (EAE) is often employed as a model to mimic the clinical manifestations of MS, mainly CNS demyelination. Coagulation is known to participate in crosstalk with inflammation and autoimmunity. We herein explored the correlation between the coagulation cascade and CNS immune diseases in vitro using primary astrocytes isolated from mice and in vivo using a mouse model of EAE. We showed that dabigatran, a clinical oral anti-coagulant drug, suppressed the thrombin-induced activation of astrocytes, and the underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs). Importantly, dabigatran effectively recovered neurological function, reduced inflammation in the spinal cord, and prevented spinal cord demyelination caused by EAE. We suggest that dabigatran, a specific inhibitor of thrombin, antagonized the effect of thrombin in astrocytes by limiting the activation of PAR-1, in turn downregulating SphK1 and disrupting S1P receptor signaling. These findings reveal critical information about the relationship between coagulation mechanisms and CNS immune diseases and will contribute to the clinical translation and development of therapeutic strategies against MS.

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Section: Discussionmentioning

confidence: 99%

Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model

Chen

Cao

Luo

et al. 2020

Front. Mol. Neurosci.

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“…The bioactive lipids lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are present in ascitic fluid of ovarian cancer patients and activate GPCRs upstream of Rac1. Elevated levels of LPA and S1P are both associated with ovarian tumor cell migration, invasion and metastasis [ 6 , 84 ] and these processes require Rac1-dependent actin remodeling. Pharmacologic inhibition of Rac1 decreased S1P-dependent ovarian tumor cell invasion [ 85 ].…”

Section: Pathways For Rac1 Activation By the Ovarian Tumor Microenmentioning

confidence: 99%

Ovarian Tumor Microenvironment Signaling: Convergence on the Rac1 GTPase

Hudson

Gillette

Kang

et al. 2018

Cancers

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The tumor microenvironment for epithelial ovarian cancer is complex and rich in bioactive molecules that modulate cell-cell interactions and stimulate numerous signal transduction cascades. These signals ultimately modulate all aspects of tumor behavior including progression, metastasis and therapeutic response. Many of the signaling pathways converge on the small GTPase Ras-related C3 botulinum toxin substrate (Rac)1. In addition to regulating actin cytoskeleton remodeling necessary for tumor cell adhesion, migration and invasion, Rac1 through its downstream effectors, regulates cancer cell survival, tumor angiogenesis, phenotypic plasticity, quiescence, and resistance to therapeutics. In this review we discuss evidence for Rac1 activation within the ovarian tumor microenvironment, mechanisms of Rac1 dysregulation as they apply to ovarian cancer, and the potential benefits of targeting aberrant Rac1 activity in this disease. The potential for Rac1 contribution to extraperitoneal dissemination of ovarian cancer is addressed.

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“… 11 Our previous in vivo and in vitro studies have shown that the lipid growth factor LPA, synthesized and secreted by the ovarian cancer cells is present in high concentration in the ascites of ovarian cancer patients. 12 , 13 , 14 With its ability to stimulate multiple oncogenic signaling pathways in ovarian cancer cells as well as cancer-associated fibroblasts, LPA has been identified as the critical growth factor present in the ovarian cancer TME. While the pleotropic effects of thymoquinone (TQ) are extensively studied, no studies thus far have investigated the anticancer effects of TQ in the presence of LPA in ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Differential effects of thymoquinone on lysophosphatidic acid-induced oncogenic pathways in ovarian cancer cells

Jayaraman

Radhakrishnan

et al. 2020

Journal of Traditional and Complementary Medicine

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Thymoquinone, a therapeutic phytochemical derived from Nigella sativa, has been shown to have a potent anticancer activity. However, it has been identified that the tumor microenvironment (TME) can attenuate the anticancer effects of thymoquinone (TQ) in ovarian cancer. Lysophosphatidic acid (LPA), a lipid growth factor present in high concentration in the TME of ovarian cancer, has been shown to regulate multiple oncogenic pathways in ovarian cancer. Taking account of the crucial role of LPA in the genesis and progression of ovarian cancer, the present study is focused on assessing the efficacy of TQ in inhibiting LPA-stimulated oncogenic pathways in ovarian cancer cells. Our results indicate that TQ is unable to attenuate LPA-stimulated proliferation or metabolic reprogramming in ovarian cancer cells. However, TQ potently inhibits the basal as well as LPA-stimulated migratory responses of the ovarian cancer cells. Furthermore, TQ abrogates the invasive migration of ovarian cancer cells induced by Gαi2, through which LPA stimulates cell migration. TQ also attenuates the activation of JNK, Src, and FAK, the downstream signaling nodes of LPA-LPAR-Gαi2 signaling pathway. In addition to establishing the differential effects of TQ in ovarian cancer cells, our results unravel the antitherapeutic role of LPA in the ovarian cancer TME could override the inhibitory effects of TQ on cell proliferation and metabolic reprogramming of ovarian cancer cells. More importantly, the concomitant finding that TQ could still sustain its inhibitory effect on LPA-stimulated invasive cell migration, points to its potential use as a response-specific therapeutic agent in ovarian cancer.

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Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment

Cited by 39 publications

References 171 publications

Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model

Dabigatran Suppresses PAR-1/SphK/S1P Activation of Astrocytes in Experimental Autoimmune Encephalomyelitis Model

Ovarian Tumor Microenvironment Signaling: Convergence on the Rac1 GTPase

Differential effects of thymoquinone on lysophosphatidic acid-induced oncogenic pathways in ovarian cancer cells

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