title: A positive feedback between activated extracellularly regulated kinase and cyclooxygenase/lipoxygenase maintains proliferation and migration of breast cancer cells.
abstract: Metastasis of breast cancer cells is the leading cause of death in breast cancer patients. Why do breast cancer cells with high metastatic potential always keep in high proliferation and migration? The endogenous signaling pathways associated with tumor metastasis remain unclear. In the present study, we address whether a link between ERK and the enzymes associated with arachidonic acid (AA) metabolism contributes to the proliferation and migration of breast cancer cells. To identify endogenous signaling pathways involved in sustaining proliferation and migration of breast cancer cells, we performed parallel studies of human breast cancer cell lines that differ in their metastatic potential. Our data showed that cell lines with high metastatic potential, including LM-MCF-7 and MDA-MB-231, exhibited significantly high, sustained levels of phosphorylated ERK (pERK) 1/2 relative to MCF-7 cells. Our findings showed that beta-catenin, cyclin D1, and survivin serve downstream effectors of pERK1/2, whereas Gi/o proteins, phospholipase C, and protein kinase C serve upstream activators of pERK1/2. In addition, AA metabolites were able to activate Gi/o proteins, phospholipase C, protein kinase C, and pERK1/2 cascades through cyclooxygenase and lipoxygenase. In contrast, activated ERK1/2 promoted AA metabolism through a positive feedback loop, which conduces to a high proliferative potential and the migration of the breast cancer cells. Together, our data provide new mechanistic insights into possible endogenous signaling metastatic signaling pathways involved in maintaining proliferation and migration of breast cancer cells.
authors.affiliation: Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin, People's Republic of China.
authors.forename: Jiacong
authors.initials: J
authors.lastname: You
authors.forename: Da
authors.initials: D
authors.lastname: Mi
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhou
authors.forename: Ling
authors.initials: L
authors.lastname: Qiao
authors.forename: Hang
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhang
authors.forename: Lihong
authors.initials: L
authors.lastname: Ye
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins; D008084:Lipoxygenase / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D010738:Type C Phospholipases / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C107489:BIRC5 protein, human; D005419:Flavonoids; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D051176:beta Catenin; D019938:Cyclin D1; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010738:Type C Phospholipases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one