Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer.
Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer.
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DOI：
10.1016/j.neo.2017.05.004
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Glunde K
中科院分区：
文献类型：
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作者：
Cheng M;Rizwan A;Jiang L;Bhujwalla ZM;Glunde K
胆碱磷脂代谢异常是癌症的标志。磁共振波谱（MRS）检测的总胆碱（tCho）信号可作为乳腺癌化疗反应的早期无创性影像学生物标志物。我们已经量化了tCho信号的各个成分，甘油磷酸胆碱（GPC），磷酸胆碱（PC）和游离胆碱（Cho），在弱转移性人MCF 7和三阴性人MDA-MB-231乳腺癌细胞中用常用化疗药物阿霉素治疗前后。虽然tCho浓度在多柔比星治疗后没有变化，但GPC显著增加，PC降低。两个磷脂酰胆碱特异性PLD酶，只有PLD 1，但不是PLD 2，mRNA被阿霉素治疗下调。对于两个报告的基因编码GPC磷酸二酯酶，GDPD 6的mRNA，但不是GDPD 5，减少阿霉素治疗后。多柔比星处理后，胆碱激酶α（ChKα）（将Cho转化为PC）的mRNA水平降低。PLD 1和ChKα蛋白水平在阿霉素处理后以浓度依赖性方式降低。用PLD 1特异性抑制剂VU 0155069处理使MCF 7和MDA-MB-231乳腺癌细胞对阿霉素诱导的细胞毒性敏感。低浓度的100 nM阿霉素增加MDA-MB-231细胞迁移。GDPD 6，而不是PLD 1或ChKα，沉默siRNA取消阿霉素诱导的乳腺癌细胞迁移。阿霉素诱导的GPC升高和PC降低是由PLD 1、GDPD 6和ChKα mRNA和蛋白表达降低引起的。我们已经证明，沉默或抑制这些基因/蛋白质可以促进药物有效性并减少药物不良反应。我们的研究结果强调了单独检测PC和GPC的重要性。
Abnormal choline phospholipid metabolism is a hallmark of cancer. The magnetic resonance spectroscopy (MRS) detected total choline (tCho) signal can serve as an early noninvasive imaging biomarker of chemotherapy response in breast cancer. We have quantified the individual components of the tCho signal, glycerophosphocholine (GPC), phosphocholine (PC) and free choline (Cho), before and after treatment with the commonly used chemotherapeutic drug doxorubicin in weakly metastatic human MCF7 and triple-negative human MDA-MB-231 breast cancer cells. While the tCho concentration did not change following doxorubicin treatment, GPC significantly increased and PC decreased. Of the two phosphatidylcholine-specific PLD enzymes, only PLD1, but not PLD2, mRNA was down-regulated by doxorubicin treatment. For the two reported genes encoding GPC phosphodiesterase, the mRNA of GDPD6, but not GDPD5, decreased following doxorubicin treatment. mRNA levels of choline kinase α (ChKα), which converts Cho to PC, were reduced following doxorubicin treatment. PLD1 and ChKα protein levels decreased following doxorubicin treatment in a concentration dependent manner. Treatment with the PLD1 specific inhibitor VU0155069 sensitized MCF7 and MDA-MB-231 breast cancer cells to doxorubicin-induced cytotoxicity. Low concentrations of 100 nM of doxorubicin increased MDA-MB-231 cell migration. GDPD6, but not PLD1 or ChKα, silencing by siRNA abolished doxorubicin-induced breast cancer cell migration. Doxorubicin induced GPC increase and PC decrease are caused by reductions in PLD1, GDPD6, and ChKα mRNA and protein expression. We have shown that silencing or inhibiting these genes/proteins can promote drug effectiveness and reduce adverse drug effects. Our findings emphasize the importance of detecting PC and GPC individually.