Molecular studies of the MR-detectable oncometabolite glycerophosphocholine

胆碱磷脂代谢在癌症中发生了深刻的变化。虽然已经投入了大量的研究 在阐明癌症中升高的磷胆碱(PC)的分子来源方面，很少有人关注 关注肿瘤代谢物甘油磷胆碱(GPC)及其基础分子生物学。高分辨率 (HR)磁共振波谱(MRS)研究表明，正常人的GPC高于PC 乳腺癌细胞中PC高于GPC。这一发现被称为“GPC to” 胆碱代谢产物恶性转化时的“PC开关”。到目前为止，基因和特异性 负责GPC中与癌症相关的变化的酶尚不清楚。细胞凝胶渗透压的变化 水平可通过甘油磷酸胆碱-磷酸二酯酶(GPC-PDE)或溶血磷脂酶(LPL)发生。 通过将HR MRS与基因沉默策略相结合，我们观察到GDPD5和GDPD5的沉默 GDPD6和GPC-PDE都是GPC-PDE，显著增加乳腺癌细胞中GPC的水平，而 减少它们的扩散、迁徙和入侵。化疗药物对乳腺癌细胞的治疗作用 阿霉素导致胆碱循环基因胆碱激酶α(Chkα)下调， 磷脂酶D 1(PLD 1)和GDPD6，从而导致GPC净增和PC下降 同时显著抑制了细胞的扩散。这些初步数据清楚地表明了一个重要的角色 GDPD5和GDPD6在乳腺癌细胞侵袭性和化疗疗效中的作用我们的 FDA批准的三种不同常用化疗药物的新初步数据表明 探索GPC作为独立于PC的治疗反应的额外生物标志物是有价值的， 当然，这将是对其他有价值的成像生物标志物的补充。我们还将调查互惠关系 致癌信号通路与GPC调节酶之间的相互作用对肿瘤至关重要 维护和发展。这项拟议的研究将为分子调控提供新的见解。 肿瘤代谢物GPC在乳腺癌中的作用，并将有助于了解其在癌症进展中的作用。我们的发现 将为解释非侵入性1H和31P MRS检测到的GPC水平提供基础 附加的转化、分期和治疗反应的补充生物标志物。GPC或关键GPC- 调节酶也可能是肿瘤转化、分期和治疗反应的有用生物标志物。 体外活组织样本。该提案中研究的酶，例如GDPD5和GDPD6，可能证明 可单独或与乳腺癌的化疗联合使用，作为抗癌靶点。

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.