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
基本信息
- 批准号:10219979
- 负责人:
- 金额:$ 37.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAttentionBiological MarkersBiologyBiopsyBreastBreast Cancer CellBreast Cancer ModelBreast Cancer PatientBreast Cancer TreatmentBreast Epithelial CellsCHK geneCancer ControlCancer PatientCell Culture TechniquesCharacteristicsCholineCholine KinaseClinicClinicalCombined Modality TherapyComplexDataDoxorubicinERBB2 geneEnzymesEpidermal Growth Factor ReceptorEstrogen receptor negativeEstrogensFDA approvedFoundationsGene SilencingGenesHormone ReceptorHumanLysophospholipaseMagnetic Resonance SpectroscopyMaintenanceMalignant - descriptorMalignant NeoplasmsMediatingMetabolicMetabolismMolecularMolecular BiologyNeoplasm MetastasisNon-Invasive Cancer DetectionOncogenicPRKCA genePaclitaxelPathway interactionsPharmaceutical PreparationsPhospholipid MetabolismPhosphorylcholineProgesteroneReceptor Protein-Tyrosine KinasesRegulationResearchResistanceResolutionRoleSP1 geneSignal PathwaySignal TransductionStagingTestingTimeTissue SampleTranscription Factor AP-1VinorelbineXenograft procedureaggressive breast canceranti-cancerbasecancer cellcancer therapycell motilitychemotherapeutic agentchemotherapyclinical effectglycerophosphocholine phosphodiesterasehypoxia inducible factor 1image guidedimaging biomarkerimprovedin vivoinsightmalignant breast neoplasmmigrationnew therapeutic targetnon-invasive imagingnovelorthotopic breast canceroverexpressionpatient derived xenograft modelphospholipase D1responseresponse biomarkerspectroscopic imagingtargeted imagingtranscription factortreatment effecttreatment responsetreatment strategytumortumor growthtumor progressiontumorigenesis
项目摘要
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
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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:
- 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
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Kristine Glunde其他文献
Kristine Glunde的其他文献
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{{ truncateString('Kristine Glunde', 18)}}的其他基金
Reprogramming of creatine metabolism in breast cancer metastasis
乳腺癌转移中肌酸代谢的重编程
- 批准号:
10569104 - 财政年份:2022
- 资助金额:
$ 37.46万 - 项目类别:
Reprogramming of creatine metabolism in breast cancer metastasis
乳腺癌转移中肌酸代谢的重编程
- 批准号:
10389302 - 财政年份:2022
- 资助金额:
$ 37.46万 - 项目类别:
timsTOF fleX with MALDI-2 for Advanced Mass Spectrometry Imaging
timsTOF fleX 与 MALDI-2 用于高级质谱成像
- 批准号:
10190407 - 财政年份:2021
- 资助金额:
$ 37.46万 - 项目类别:
Hypoxia-derived molecular MSI signatures to predict breast cancer outcome
缺氧衍生的分子 MSI 特征可预测乳腺癌结果
- 批准号:
9390214 - 财政年份:2017
- 资助金额:
$ 37.46万 - 项目类别:
Hypoxia-derived molecular MSI signatures to predict breast cancer outcome
缺氧衍生的分子 MSI 特征可预测乳腺癌结果
- 批准号:
10227792 - 财政年份:2017
- 资助金额:
$ 37.46万 - 项目类别:
Multi-scale Molecular Imaging of the Degradome in Breast Tumors
乳腺肿瘤降解组的多尺度分子成像
- 批准号:
8835062 - 财政年份:2011
- 资助金额:
$ 37.46万 - 项目类别:
Multi-scale Molecular Imaging of the Degradome in Breast Tumors
乳腺肿瘤降解组的多尺度分子成像
- 批准号:
8657892 - 财政年份:2011
- 资助金额:
$ 37.46万 - 项目类别:
Multi-scale Molecular Imaging of the Degradome in Breast Tumors
乳腺肿瘤降解组的多尺度分子成像
- 批准号:
8455704 - 财政年份:2011
- 资助金额:
$ 37.46万 - 项目类别:
Multi-scale Molecular Imaging of the Degradome in Breast Tumors
乳腺肿瘤降解组的多尺度分子成像
- 批准号:
8186734 - 财政年份:2011
- 资助金额:
$ 37.46万 - 项目类别:
Multi-scale Molecular Imaging of the Degradome in Breast Tumors
乳腺肿瘤降解组的多尺度分子成像
- 批准号:
8286171 - 财政年份:2011
- 资助金额:
$ 37.46万 - 项目类别:
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