Molecular studies of the MR-detectable oncometabolite glycerophosphocholine

MR 可检测肿瘤代谢物甘油磷酸胆碱的分子研究

• 批准号: 10219979
• 负责人: Kristine Glunde
• 金额: $ 37.46万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-09 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10219979
• 关键词: Affect; Attention; Biological Markers; Biology; Biopsy; Breast; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; Breast Epithelial Cells; CHK gene; Cancer Control; Cancer Patient; Cell Culture Techniques; Characteristics; Choline; Choline Kinase; Clinic; Clinical; Combined Modality Therapy; Complex; Data; Doxorubicin; ERBB2 gene; Enzymes; Epidermal Growth Factor Receptor; Estrogen receptor negative; Estrogens; FDA approved; Foundations; Gene Silencing; Genes; Hormone Receptor; Human; Lysophospholipase; Magnetic Resonance Spectroscopy; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Molecular Biology; Neoplasm Metastasis; Non-Invasive Cancer Detection; Oncogenic; PRKCA gene; Paclitaxel; Pathway interactions; Pharmaceutical Preparations; Phospholipid Metabolism; Phosphorylcholine; Progesterone; Receptor Protein-Tyrosine Kinases; Regulation; Research; Resistance; Resolution; Role; SP1 gene; Signal Pathway; Signal Transduction; Staging; Testing; Time; Tissue Sample; Transcription Factor AP-1; Vinorelbine; Xenograft procedure; aggressive breast cancer; anti-cancer; base; cancer cell; cancer therapy; cell motility; chemotherapeutic agent; chemotherapy; clinical effect; glycerophosphocholine phosphodiesterase; hypoxia inducible factor 1; image guided; imaging biomarker; improved; in vivo; insight; malignant breast neoplasm; migration; new therapeutic target; non-invasive imaging; novel; orthotopic breast cancer; overexpression; patient derived xenograft model; phospholipase D1; response; response biomarker; spectroscopic imaging; targeted imaging; transcription factor; treatment effect; treatment response; treatment strategy; tumor; tumor growth; tumor progression; tumorigenesis

Choline phospholipid metabolism is profoundly altered in cancer. While a lot of research has been devoted toward elucidating the molecular origins of elevated phosphocholine (PC) in cancer, little attention has been paid to the oncometabolite glycerophosphocholine (GPC) and its underlying molecular biology. High-resolution (HR) magnetic resonance spectroscopy (MRS) studies have shown that GPC is higher than PC in normal breast epithelial cells, whereas PC is higher than GPC in breast cancer cells. This finding is known as “GPC to PC switch” in the choline metabolite profile upon malignant transformation. To date, the genes and specific enzymes responsible for the cancer-related alterations in GPC are unknown. The changes in cellular GPC levels could occur through glycerophosphocholine-phosphodiesterase (GPC-PDE) or lysophospholipase (LPL). By combining HR MRS with gene silencing strategies, we have observed that silencing of GDPD5 and GDPD6, both of which are GPC-PDEs, significantly increased the GPC levels in breast cancer cells, while reducing their proliferation, migration, and invasion. Chemotherapy treatment of breast cancer cells with doxorubicin resulted in down-modulation of the choline cycle genes choline kinase alpha (Chkα), phospholipase D1 (PLD1), and GDPD6, thereby resulting in a net increase of GPC and a decrease in PC along with a significant inhibition of proliferation. These preliminary data clearly point towards an important role of GDPD5 and GDPD6 in breast cancer cell aggressiveness and treatment response to chemotherapy. Our new preliminary data with three different commonly used FDA-approved chemotherapeutic agents indicate that there is value in exploring GPC as an additional biomarker of treatment response independent of PC, which, of course, would be in addition to other valuable imaging biomarkers. We will also investigate the reciprocal interactions between oncogenic signaling pathways and GPC-regulating enzymes that are critical for tumor maintenance and progression. The proposed research will provide novel insight into the molecular regulation of the oncometabolite GPC in breast cancer, and will help understand its role in cancer progression. Our findings will provide the foundation for interpreting GPC levels detected by noninvasive 1H and 31P MRS as an additional complementary biomarker of transformation, staging, and response to therapy. GPC or critical GPC- regulating enzymes may also be useful biomarkers of transformation, staging, and response to therapy in biopsied tissue samples ex vivo. The enzymes studied in this proposal, e.g. GDPD5 and GDPD6, may prove useful as anticancer targets, either alone or in combination with chemotherapy treatment of breast cancer.

胆碱磷脂代谢在癌症中发生了深刻的改变。虽然已经进行了大量的研究

项目成果

Silencing of the glycerophosphocholine phosphodiesterase GDPD5 alters the phospholipid metabolite profile in a breast cancer model in vivo as monitored by (31) P MRS.

• DOI: 10.1002/nbm.3106
• 发表时间: 2014-06
• 期刊: NMR IN BIOMEDICINE
• 影响因子: 2.9
• 作者: Wijnen, J. P.;Jiang, L.;Greenwood, T. R.;Cheng, M.;Doepkens, M.;Cao, M. D.;Bhujwalla, Z. M.;Krishnamachary, B.;Klomp, D. W. J.;Glunde, K.
• 通讯作者: Glunde, K.

Targeting choline phospholipid metabolism: GDPD5 and GDPD6 silencing decrease breast cancer cell proliferation, migration, and invasion.

• DOI: 10.1002/nbm.3573
• 发表时间: 2016-08
• 期刊: NMR in biomedicine
• 影响因子: 2.9
• 作者: Cao MD;Cheng M;Rizwan A;Jiang L;Krishnamachary B;Bhujwalla ZM;Bathen TF;Glunde K
• 通讯作者: Glunde K