Treatment with the MEK inhibitor U0126 induces decreased hyperpolarized pyruvate to lactate conversion in breast, but not prostate, cancer cells.
Treatment with the MEK inhibitor U0126 induces decreased hyperpolarized pyruvate to lactate conversion in breast, but not prostate, cancer cells.
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DOI：
10.1002/nbm.2848
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发表时间：
2013-03
影响因子：
2.9
通讯作者：
Ronen, Sabrina M.
中科院分区：
文献类型：
--
作者：
Lodi, Alessia;Woods, Sarah M.;Ronen, Sabrina M.
细胞代谢的改变越来越被认为是癌症的标志，并被用于诊断工具和靶向治疗的开发。最近，13 C磁共振波谱（MRS）可检测的超极化丙酮酸转化为乳酸在模型中被验证为一种非侵入性的成像方法，用于检测肿瘤和治疗反应，并成功地通过了I期临床试验。迄今为止，对治疗的反应与超极化乳酸产生的下降相关。在这里，我们监测了MEK抑制剂U 0126在前列腺癌和乳腺癌细胞中的治疗效果。治疗后，我们观察到与对照相比，治疗的MCF-7乳腺癌细胞中超极化13 C标记的通量下降了31%。相反，出乎意料的是，在经处理的PC 3前列腺癌细胞中，通量增加至167%。为了从机制上解释这些观察结果，我们研究了已知影响丙酮酸转化为乳酸的不同因素的治疗诱导的变化。NADH水平保持不变，而乳酸脱氢酶的表达和活性，以及细胞内的乳酸增加，在两个细胞系中，提供了一个解释升高的超极化的乳酸在PC 3细胞中观察到。介导丙酮酸转运的MCT 1的表达在处理的MCF-7中下降，但在PC 3细胞中没有。这鉴定了丙酮酸转运作为U 0126处理的MCF-7细胞中的速率限制，并解释了处理后在这些细胞中观察到的超极化乳酸的下降。我们的研究结果强调了MEK和代谢之间相互作用的复杂性，以及在超极化13 C MRS可用于监测治疗诱导的分子反应之前需要进行机制验证。
Alterations in cell metabolism are increasingly recognized as a hallmark of cancer and are being exploited for the development of diagnostic tools and targeted therapeutics. Recently, 13C magnetic resonance spectroscopy (MRS)-detectable hyperpolarized pyruvate to lactate conversion was validated in models as a noninvasive imaging method for the detection of tumors and treatment response, and successfully passed phase I clinical trials. To date, response to treatment was associated with a drop in hyperpolarized lactate production. Here, we monitored the effect of treatment with the MEK inhibitor U0126 in prostate and breast cancer cells. Following treatment we observed a 31% drop in flux of hyperpolarized 13C label in treated MCF-7 breast cancer cells compared to controls. In contrast and unexpectedly, flux increased to 167% in treated PC3 prostate cancer cells. To mechanistically explain these observations we investigated treatment-induced changes in the different factors known to affect pyruvate to lactate conversion. NADH levels remained unchanged whereas lactate dehydrogenase expression and activity as well as intracellular lactate increased in both cell lines, providing an explanation for the elevated hyperpolarized lactate observed in PC3 cells. The expression of MCT1, which mediates pyruvate transport, dropped in treated MCF-7 but not in PC3 cells. This identifies pyruvate transport as rate limiting in U0126-treated MCF-7 cells and explains the drop in hyperpolarized lactate observed in those cells following treatment. Our findings highlight the complexity of interactions between MEK and metabolism, and the need for mechanistic validation before hyperpolarized 13C MRS can be used for monitoring treatment-induced molecular responses.
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影响因子：
3.7
作者：
Lodi A;Ronen SM
通讯作者：
Ronen SM
影响因子：
11.2
作者：
Beloueche-Babari, M;Jackson, LE;Ronen, SM
通讯作者：
Ronen, SM
影响因子：
3.3
作者：
Day, Sam E.;Kettunen, Mikko I.;Brindle, Kevin M.
通讯作者：
Brindle, Kevin M.
影响因子：
82.9
作者：
Day, Sam E.;Kettunen, Mikko I.;Brindle, Kevin M.
通讯作者：
Brindle, Kevin M.
影响因子：
3.3
作者：
Gallagher, Ferdia A.;Kettunen, Mikko I.;Brindle, Kevin M.
通讯作者：
Brindle, Kevin M.