Lipid Generation and Signaling in Ovarian Cancer

Xu, Yan; Wang, Dongmei; Wang, Zeneng

doi:10.1007/978-0-387-98094-2_12

Cited by 6 publications

(7 citation statements)

References 140 publications

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“…LPA is involved in many aspects of EOC pathogenesis and development and is a major target for EOC treatment [14,51,52]. Further study of the signaling mechanisms of LPA will be important for basic science as well as for translational applications.…”

Section: Discussionmentioning

confidence: 99%

The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells

2013

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BackgroundThe Hippo-YAP signaling pathway is altered and implicated as oncogenic in many human cancers. However, extracellular signals that regulate the mammalian Hippo pathway have remained elusive until very recently when it was shown that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) ligands including lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P). LPA inhibits Lats kinase activity in HEK293 cells, but the potential involvement of a protein phosphatase was not investigated. The extracellular regulators of YAP dephosphorylation (dpYAP) and nuclear translocation in epithelial ovarian cancer (EOC) are essentially unknown.ResultsWe showed here that LPA dose- and time-dependently induced dpYAP in human EOC cell lines OVCA433, OVCAR5, CAOV3, and Monty-1, accompanied by increased YAP nuclear translocation. YAP was involved in LPA-induced migration and invasion of EOC cells and LPA3 was a major LPA receptor mediating the migratory effect. We demonstrated that G13, but not or to a lesser extent G12, Gi or Gq, was necessary for LPA-induced dpYAP and its nuclear translocation and that RhoA-ROCK, but not RhoB, RhoC, Rac1, cdc42, PI3K, ERK, or AKT, were required for the LPA-dpYAP effect. In contrast to results in HEK293 cells, LPA did not inhibit Mst and Lats kinase in OVCA433 EOC cells. Instead, protein phosphatase 1A (PP1A) acted down-stream of RhoA in LPA-induction of dpYAP. In addition, we identified that amphiregulin (AREG), a down-stream target of YAP which activated EGF receptors (EGFR), mediated an LPA-stimulated and EGFR-dependent long-term (16 hr) cell migration. This process was transcription- and translation-dependent and was distinct from a transcription- and YAP-independent short-term (4 hr) cell migration. EOC tissues had reduced pYAP levels compared to normal and benign ovarian tissues, implying the involvement of dpYAP in EOC pathogenesis, as well as its potential marker and/or target values.ConclusionsA novel LPA-LPA3-G13-RhoA-ROCK-PP1A-dpYAP-AREG-EGFR signaling pathway was linked to LPA-induced migration of EOC cells. Reduced pYAP levels were demonstrated in human EOC tumors as compared to both normal ovarian tissues and benign gynecologic masses. Our findings support that YAP is a potential marker and target for developing novel therapeutic strategies against EOC.

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Section: Discussionmentioning

confidence: 99%

The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells

2013

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“…Accumulation of malignant ascites in the peritoneal cavity is common, particularly in women with late-stage EOC. Thus metastasizing EOC cells exist in a milieu rich in inflammatory cells [88] and growth/signalling factors, including VEGF [89–91], EGF [11,92], TGFα, TGFβ [93,94] and LPA [23,95], providing ample opportunity for cross-talk between signalling networks. Ascites accumulation also modifies peritoneal mechanobiology, altering the force environment of both metastatic tumour cells and peritoneal mesothelium [96,97].…”

Section: Microenvironmental Activation Of the Wnt Pathwaymentioning

confidence: 99%

“…LPA, a bioactive lipid signalling molecule, plays a role in numerous cell processes, including proliferation, migration, adhesion and cell survival [23–26,99,100], by acting at a family of GPCRs known as LPARs (LPA receptors) [101,102]. LPA has wide-ranging influence on cell physiology and pathophysiology, including increases in cytokine and growth factor expression, alteration of surface-protein trafficking and modulation of transcription [103,104].…”

Section: Microenvironmental Activation Of the Wnt Pathwaymentioning

confidence: 99%

“…LPA has wide-ranging influence on cell physiology and pathophysiology, including increases in cytokine and growth factor expression, alteration of surface-protein trafficking and modulation of transcription [103,104]. LPA, which is produced by both normal and malignant cells, is present in high concentration (2–80 μM) in ascites and serum from 98% of ovarian cancer patients, including those with early-stage disease [23,26,104–108]. Furthermore, increasing LPA expression is correlated with poor prognosis, suggesting its potential role as a therapeutic biomarker [109].…”

Section: Microenvironmental Activation Of the Wnt Pathwaymentioning

confidence: 99%

“…Cytokine-mediated activation of NF-κB (nuclear factor κB) is also commonly detected in ovarian tumours, leading to up-regulation of anti-apoptotic and antioxidant gene products [22]. Lipid signalling via interaction of LPA (lysophosphatidic acid) with LPA GPCRs is a potent means of microenvironmental regulation, as LPA can be produced by tumour cells as well as stromal components, including mesothelial and inflammatory cells [23]. LPA binds to surface GPCRs, leading to activation of diverse signalling pathways depending on the LPA receptor complement and the specific G-proteins expressed by the cell.…”

Section: Introductionmentioning

confidence: 99%

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Diverse mechanisms for activation of Wnt signalling in the ovarian tumour microenvironment

Barbolina

Burkhalter

Stack

2011

Biochemical Journal

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Wnt signalling pathways have been shown to play key roles in both normal development and tumorigenesis. Progression of many human cancers is associated with defined mutations in Wnt pathway components that result in dysregulated β-catenin-mediated gene transcription. Although Wnt pathway mutations are rare in epithelial ovarian cancer (with the exception of the endometrioid histotype), accumulating evidence supports a role for Wnt signalling in ovarian tumorigenesis in the absence of genetic mutations. The present review summarizes evidence in support of activated Wnt signalling in ovarian tumours and discusses alternative mechanisms for Wnt pathway activation in the ovarian tumour microenvironment.

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Lipids

Schiller¹,

Fuchs²

2013

Maldi MS

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Lipid Generation and Signaling in Ovarian Cancer

Cited by 6 publications

References 140 publications

The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells

The role of LPA and YAP signaling in long-term migration of human ovarian cancer cells

Diverse mechanisms for activation of Wnt signalling in the ovarian tumour microenvironment

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