Cheng Menglin, Rizwan Asif, Jiang Lu, Bhujwalla Zaver M, Glunde Kristine
Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Division of Cancer Imaging Research, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Neoplasia. 2017 Aug;19(8):617-627. doi: 10.1016/j.neo.2017.05.004. Epub 2017 Jun 24.
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.
异常的胆碱磷脂代谢是癌症的一个标志。磁共振波谱（MRS）检测到的总胆碱（tCho）信号可作为乳腺癌化疗反应的早期非侵入性成像生物标志物。我们已经对低转移性人MCF7和三阴性人MDA-MB-231乳腺癌细胞在用常用化疗药物阿霉素治疗前后的tCho信号的各个成分，即甘油磷酸胆碱（GPC）、磷酸胆碱（PC）和游离胆碱（Cho）进行了定量。虽然阿霉素治疗后tCho浓度没有变化，但GPC显著增加而PC减少。在两种磷脂酰胆碱特异性磷脂酶D（PLD）酶中，只有PLD1的mRNA被阿霉素治疗下调，而PLD2没有。对于两个报道的编码GPC磷酸二酯酶的基因，阿霉素治疗后GDPD6的mRNA减少，而GDPD5没有。将Cho转化为PC的胆碱激酶α（ChKα）的mRNA水平在阿霉素治疗后降低。阿霉素治疗后PLD1和ChKα蛋白水平以浓度依赖的方式降低。用PLD1特异性抑制剂VU0155069处理可使MCF7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100 nM的阿霉素增加了MDA-MB-231细胞的迁移。通过小干扰RNA（siRNA）沉默GDPD6而非PLD1或ChKα可消除阿霉素诱导的乳腺癌细胞迁移。阿霉素诱导的GPC增加和PC减少是由PLD1、GDPD6和ChKα mRNA及蛋白表达的降低引起的。我们已经表明，沉默或抑制这些基因/蛋白可以提高药物疗效并减少药物不良反应。我们的发现强调了单独检测PC和GPC的重要性。
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