Glycolytic signaling of p38gamma in breast cancer

乳腺癌中 p38gamma 的糖酵解信号传导

• 批准号: 10618781
• 负责人: GUAN CHEN
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618781
• 关键词: 6-Phosphofructo-2-kinase; Binding; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Cells; Clinic; Clinical; Collaborations; Combined Modality Therapy; Complex; Data; Dose; Enzymes; Estrogen Receptors; Family member; Female; Fructose-2,6-bisphosphatase; Gene Expression; Genes; Genetic; Genetic Transcription; Glycolysis; Growth; Healthcare; Individual; Knock-out; Link; MAP Kinase Gene; MAPK12 gene; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolic Pathway; Mus; Oncogenes; Outcome; Pathogenesis; Pathologic; Pathway interactions; Phosphorylation; Phosphotransferases; Pirfenidone; Progesterone Receptors; Prognosis; Protein Family; Proteins; Proteomics; Public Health; RNA; Research; Role; SLC2A1 gene; Signal Transduction; Signal Transduction Pathway; Specimen; Subgroup; Testing; Therapeutic; Therapeutic Intervention; Tissues; Up-Regulation; Veterans; Warburg Effect; aerobic glycolysis; functional group; glucose uptake; improved; inhibitor; malignant breast neoplasm; molecular targeted therapies; mouse genetics; new therapeutic target; novel; novel therapeutic intervention; overexpression; pharmacologic; polyoma middle tumor antigen; public database; screening; targeted treatment; therapeutic target; therapeutically effective; triple-negative invasive breast carcinoma; tumorigenesis

Triple-negative breast cancer (TNBC) does not express estrogen receptor (ER), progesterone receptor (PR) and Her2 as therapeutic targets and consequently has the worst prognosis among all types of breast cancers. Metabolic reprogramming toward aerobic glycolysis (also called the Warburg effect) is a hallmark of cancer, which is further activated in TNBC. Although aerobic glycolysis may be therapeutically targeted, the druggable pathway has not been identified. p38 is a TNBC oncogene and stimulates glucose uptake and metabolic adaption. This proposal will test the hypothesis that p38 promotes TNBC oncogenesis by stimulating PFKFB3/GLUT1-dependent aerobic glycolysis. This hypothesis is based on the following findings: 1) p38 stimulates glucose transporter 1 (GLUT1) expression and increases glucose uptake; 2) p38 promotes TNBC oncogenesis; 3) TNBCs are highly glycolytic with elevated PFKFB3 and GLUT1 expression; 4) p38 binds PFKFB3, a key glycolytic activator, in TNBC cells, whereas it interacts with much less glycolytic three family members (PFKFB1, 2 and 4) in non- TNBC cells; 5) MS/MS analysis identifies that p38 phosphorylates PFKFB3 at S467 leading to its stabilization, whereas data from public data-base shows that p38 gene expression is correlated with GLUT1 in invasive breast cancer tissues; 6) conditional p38 knockout (KO) inhibits tumorigenesis in a TNBC-like PyMT mouse genetic breast cancer model and decreases PFKFB3/GLUT1 expression; 7) p38 overexpression in TNBC cells increases PFKFB3/GLUT1 abundance, promotes their interaction, and stimulates ECAR (an indicator of glycolysis), indicating its activity of stimulating aerobic glycolysis by forming a ternary complex; and 8) pharmacological p38 and PFKFB3 inhibitors cooperatively decrease p-PFKFB3/PFKFB3/GLUT1 levels and inhibit TNBC growth in a manner dependent on p38. These results together indicate that p38 links aerobic glycolysis and TNBC oncogenesis through activating PFKFB3 and GLUT1. We will test this hypothesis by targeting the following aims: AIM 1 will investigate if p38 links aerobic glycolysis and TNBC oncogenesis through interaction with PFKFB3 and stimulating of PFKFB3 phosphorylation at S467; AIM 2 will determine if p38 cooperates with both PFKFB3 and GLUT1 to promote aerobic glycolysis and TNBC oncogenesis by stimulating a S467-dependent ternary-complex; and AIM 3 will determine if the p38-PFKFB3 kinase cascade is a therapeutic target for TNBC and if the p38/PFKFB3/Glut1 co-upregulation with elevated p-PFKFB3 identifies a subgroup of TNBC with a worse prognosis in clinic. These studies will demonstrate if the p38-PFKFB3 kinase cascade is a novel therapeutic target for TNBC and reveal if a combined application of p38/PFKFB3 pharmacological inhibitors is a potential effective therapeutic strategy that will impact TNBC clinical outcome and veteran health care.

三阴性乳腺癌（TNBC）不表达雌激素受体（ER）、孕激素受体（PR）