Abstract
Abstract The magnetic resonance spectroscopy (MRS)-detected total choline (tCho) signal is a promising non-invasive surrogate marker able to predict chemotherapy response in breast cancer patients early on. However, the molecular mechanisms by which common chemotherapeutic drugs affect the tCho signal, which consists of glycerophosphocholine (GPC), phosphocholine (PC), and free choline (Cho), are mostly unknown. Here we have employed some widely used cancer chemotherapeutic drugs such as doxorubicin, paclitaxel, and vinorelbine to treat triple-negative human MDA-MB-231 breast cancer cells to elucidate their molecular effects on choline phospholipid metabolism. High-resolution (HR) 1H MRS of water-soluble cell extracts was employed to detect changes in cellular choline metabolite profiles, and quantitative RT-PCR (qRT-PCR) to assess the corresponding changes in the expression levels of choline-metabolizing enzymes. After 48 hours of doxorubicin treatment, the GPC levels in MDA-MB-231 cells significantly increased, while PC level decreased, and the tCho concentration remained unchanged. Vinorelbine treatment displayed a comparable effect to doxorubicin, but the GPC increase and PC decrease occurred to a lesser extent. Paclitaxel treatment caused an increased GPC level along with an unaltered PC level, leading to a slightly increased tCho level. In all these cases, the PC/GPC ratio decreased from 3.5 in the control to about 2.0 in paclitaxel- or vinorelbine-treated samples, to about 1.0 in doxorubicin-treated samples. qRT-PCR-detected mRNA expression levels showed that GDPD6 and Chkα were downregulated by doxorubicin. GDPD5, GDPD6, and Chkα genes displayed a reduced mRNA expression level following vinorelbine treatment, while no significant change in these three genes was detected after paclitaxel treatment. For comparison, the known GDPD6 inhibitor dipyridamole significantly increased cellular GPC levels, but, as expected, did not affect GDPD6 mRNA expression levels as it acts as an enzyme inhibitor. Our study demonstrates that choline containing metabolites change differently depending on the type of drug used for breast cancer treatment. However, all tested chemotherapeutic treatments resulted in metabolic alteration away from the ‘cholinic phenotype’, which was caused in some cases by decreases in expression of Chkα, GDPD6, and GDPD5 following drug treatment. The choline metabolite concentrations of GPC and/or PC and/or the PC/GPC ratio may serve as non-invasive surrogate makers of therapeutic response in triple-negative breast cancer patients undergoing chemotherapy. Note: This abstract was not presented at the meeting. Citation Format: Menglin Cheng, Zaver M. Bhujwalla, Kristine Glunde. Distinct molecular effects of chemotherapeutic agents on choline phospholipid metabolism of triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2120. doi:10.1158/1538-7445.AM2017-2120
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