Abstract
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.
Highlights
Most cancer-associated mortality is caused by metastatic dissemination of primary tumors and the outgrowth of secondary tumors at distant sites
Diacylglycerol kinase a (DGKa) Is Necessary for SDF-1a-induced Cell Invasion We previously showed that DGKa is necessary for matrix invasion promoted by Epidermal Growth Factor (EGF) [15] or Hepatocyte Growth Factor (HGF) in MDA-MB-231 breast carcinoma cells [27]
Several studies pointed out DGKa 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]
Summary
Most cancer-associated mortality is caused by metastatic dissemination of primary tumors and the outgrowth of secondary tumors at distant sites. Among the microenvironment signals sustaining the invasive phenotype of cancer cells, stromal cellderived factor-1a (SDF-1a, named CXCL12), plays a major role in promoting cancer metastasis in several cancers, including breast cancer [1]. The chemotactic and invasive activity of SDF1a/CXCR4 is mediated by both Ga13-mediated activation of RhoA and Gai-mediated activation of Rac via DOCK180/ ELMO, which regulate cytoskeletal remodeling [5,6]. In gastric cancer cells SDF-1a invasive and proliferative activity is stimulated by Gai- and PI3Kb-mediated activation of mTOR complex 1, which contributes to Rac activation as well [9]. Neither the mechanisms by which SDF-1a stimulates aPKCs nor their role in SDF-1a invasive signaling in breast cancer cells have been elucidated
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