Diacylglycerol kinase α mediates 17-β-estradiol-induced proliferation, motility, and anchorage-independent growth of Hec-1A endometrial cancer cell line through the G protein-coupled estrogen receptor GPR30

Filigheddu, Nicoletta; Sampietro, Sara; Chianale, Federica; Porporato, Paolo E.; Gaggianesi, Miriam; Gregnanin, Ilaria; Rainero, Elena; Ferrara, Michele; Perego, Beatrice; Riboni, Francesca; Baldanzi, Gianluca; Graziani, Andrea; Surico, N

doi:10.1016/j.cellsig.2011.07.009

Cited by 35 publications

(26 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In normal epithelia, endothelia and lymphocytes DGKα activity is required to convey proliferative [17], [38], [39] and migratory [16]–[18], [22], [23] signaling. Several studies pointed out DGKα involvement in cancer showing that its activity is necessary in vivo for glioblastoma and hepatocellular carcinoma progression [13], and in vitro for proliferation and survival of endometrial carcinoma [21], anaplastic large cell lymphoma [19], and melanoma [40]. Moreover, DGKα activity mediates matrix invasion sustained by p53 pro-metastatic mutations in cancer cells [15].…”

Section: Discussionmentioning

confidence: 99%

“…DGKα is activated and recruited to the membrane by growth factors, estrogen and tyrosine kinase oncogenes through Src-mediated phosphorylation. Upon growth factor stimulation, activation of DGKα mediates cell migration, invasion and anchorage-independent growth [16]–[21]. Indeed, activation of DGKα is a central element of a novel lipid signaling pathway involving PA-mediated recruitment at the plasma membrane and activation of aPKCs in a complex with RhoGDI and Rac1, thus providing a positional signal regulating Rac1 activation and association to the membrane [22], [23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Diacylglycerol Kinase α/Atypical PKC/β1 Integrin Pathway in SDF-1α Mammary Carcinoma Invasiveness

et al. 2014

Self Cite

View full text Add to dashboard Cite

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Diacylglycerol Kinase α/Atypical PKC/β1 Integrin Pathway in SDF-1α Mammary Carcinoma Invasiveness

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Moreover the exclusive localization of PIP 2 in the apical membrane (Bryant and Mostov, 2008;Gá lvez-Santisteban et al, 2012) should limit the chance for unexpected effects of DGK inhibitors. Interestingly, this target has been recently proposed to treat inflammation, coagulation, and cancer (Holden et al, 2011;Marumo et al, 2012;Filigheddu et al, 2011) with no reported toxicity.…”

Section: Discussionmentioning

confidence: 99%

High-Content siRNA Screen Reveals Global ENaC Regulators and Potential Cystic Fibrosis Therapy Targets

Almaça

Faria

Sousa

et al. 2013

Cell

View full text Add to dashboard Cite

Dysfunction of ENaC, the epithelial sodium channel that regulates salt and water reabsorption in epithelia, causes several human diseases, including cystic fibrosis (CF). To develop a global understanding of molecular regulators of ENaC traffic/function and to identify of candidate CF drug targets, we performed a large-scale screen combining high-content live-cell microscopy and siRNAs in human airway epithelial cells. Screening over 6,000 genes identified over 1,500 candidates, evenly divided between channel inhibitors and activators. Genes in the phosphatidylinositol pathway were enriched on the primary candidate list, and these, along with other ENaC activators, were examined further with secondary siRNA validation. Subsequent detailed investigation revealed ciliary neurotrophic factor receptor (CNTFR) as an ENaC modulator and showed that inhibition of (diacylglycerol kinase, iota) DGKι, a protein involved in PiP2 metabolism, downgrades ENaC activity, leading to normalization of both Na+ and fluid absorption in CF airways to non-CF levels in primary human lung cells from CF patients.

show abstract

“…It is possible that DGKα mediates a number of oncogenic stimuli. DGKα is activated by estrogen signaling in endometrial CA (38), and it promotes cell invasiveness downstream of SDF-1α and HGF (39). Calcium plays a well-established and important role in activation of DGKα.…”

Section: Introductionmentioning

confidence: 99%

Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer

Purow

2015

Clinical Cancer Research

View full text Add to dashboard Cite

Lipid kinases have largely been neglected as targets in cancer, and an increasing number of reports suggest diacylglycerol kinase alpha (DGKα) may be one with promising therapeutic potential. DGKα is one of ten DGK family members that convert diacylglycerol (DAG) to phosphatidic acid (PA), and both DAG and PA are critical lipid second messengers in the plasma membrane. A host of important oncogenic proteins and pathways affect cancer cells in part through DGKα, including the c-Met and VEGF receptors. Others partially mediate the effects of DGKα inhibition in cancer, such as mTOR and HIF-1α. DGKα inhibition can directly impair cancer cell viability, inhibits angiogenesis, and notably may also boost T cell activation and enhance cancer immunotherapies. While two structurally similar inhibitors of DGKα were established decades ago, they have seen minimal in vivo usage and it is unlikely that either of these older DGKα inhibitors will have utility for cancer. An abandoned compound that also inhibits serotonin receptors may have more translational potential as a DGKα inhibitor, but more potent and specific DGKα inhibitors are sorely needed. Other DGK family members may also provide therapeutic targets in cancer, but require further investigation.

show abstract

Diacylglycerol kinase α mediates 17-β-estradiol-induced proliferation, motility, and anchorage-independent growth of Hec-1A endometrial cancer cell line through the G protein-coupled estrogen receptor GPR30

Cited by 35 publications

References 41 publications

The Diacylglycerol Kinase α/Atypical PKC/β1 Integrin Pathway in SDF-1α Mammary Carcinoma Invasiveness

The Diacylglycerol Kinase α/Atypical PKC/β1 Integrin Pathway in SDF-1α Mammary Carcinoma Invasiveness

High-Content siRNA Screen Reveals Global ENaC Regulators and Potential Cystic Fibrosis Therapy Targets

Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer

Contact Info

Product

Resources

About