Molecular studies of the MR-detectable oncometabolite glycerophosphocholine

胆碱磷脂代谢在癌症中发生了深刻的改变。虽然很多研究都致力于 为了阐明癌症中磷酸胆碱（PC）升高的分子起源， 对癌代谢物甘油磷酸胆碱（GPC）及其基础分子生物学的研究。高分辨率 (HR)磁共振波谱（MRS）研究表明，在正常人中，GPC高于PC。 乳腺癌细胞中PC高于GPC。这一发现被称为“GPC， 恶性转化后胆碱代谢物谱中的“PC开关”。到目前为止，基因和特定的 负责GPC中癌症相关改变的酶是未知的。细胞GPC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GDPD 5和 GDPD 6，两者都是GPC-PDE，显著增加了乳腺癌细胞中的GPC水平，而 减少它们的扩散、迁移和入侵。乳腺癌细胞的化疗治疗 阿霉素导致胆碱循环基因胆碱激酶α（Chkα）的下调， 磷脂酶D1（PLD 1）和GDPD 6，从而导致GPC的净增加和PC的减少 沿着显著的增殖抑制。这些初步数据清楚地表明， GDPD 5和GDPD 6在乳腺癌细胞侵袭性和对化疗的治疗反应中的作用。我们 FDA批准的三种常用化疗药物的新的初步数据表明， 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，这是对其他有价值的成像生物标志物的补充。我们还将研究互惠 致癌信号通路和GPC调节酶之间的相互作用对肿瘤至关重要 保持和进步。这项研究将为人类免疫系统的分子调控提供新的见解。 癌代谢物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。我们的研究结果 将为解释非侵入性1H和31 P MRS检测到的GPC水平提供基础， 转化、分期和对治疗的反应的额外补充生物标志物。GPC或临界GPC- 调节酶也可能是肿瘤转化、分期和对治疗反应的有用生物标志物。 离体活检组织样品。在该提议中研究的酶，例如GDPD 5和GDPD 6，可以证明 可单独或与乳腺癌的化疗治疗组合用作抗癌靶。

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.