Metabolic consequences of treatment with AKT inhibitor perifosine in breast cancer cells.
Metabolic consequences of treatment with AKT inhibitor perifosine in breast cancer cells.
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DOI：
10.1002/nbm.1764
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发表时间：
2012-02
影响因子：
2.9
通讯作者：
Ronen, Sabrina M.
中科院分区：
文献类型：
--
作者：
Su, Judy S.;Woods, Sarah M.;Ronen, Sabrina M.
关键词：
PI3K/Akt通路的激活与许多人类癌症的发生有关。因此，许多新兴疗法针对这一途径。先前的研究表明，在PI3K水平上靶向PI3K/Akt通路与磷脂胆碱（PCho）的下降和超极化乳酸生成的减少有关。然而，在Akt水平上靶向PI3K下游的后果尚未被研究。Perifosine是一种临床试验中的抗癌烷基磷脂。它通过抑制Akt的磷酸化起作用，也被证明可以抑制CTP：磷脂胆碱胞基转移酶（CT）。本研究的目的是确定在MCF-7乳腺癌细胞中使用perifosine治疗的mrs可检测代谢后果。我们发现，perifosine处理导致PCho从30±5 fmol/细胞下降到15±1 fmol/细胞，下降了51±5%，并且新生合成的PCho也有类似的下降。这与胆碱激酶（ChoK）活性和ChoKα表达的下降有关。CT抑制不能排除，但可能不是导致PCho改变的原因。我们还发现细胞内乳酸水平从2.7±0.5 fmol/细胞下降到1.5±0.3 fmol/细胞，细胞外乳酸水平也有类似程度的下降。这些发现与乳酸脱氢酶表达下降一致，并与缺氧诱导因子(HIF)-1α活性下降有关。因此，酪氨酸处理后PCho和乳酸生成的下降是通过HIF-1α的下降介导的，HIF-1α是ChoK和乳酸脱氢酶的转录因子。代谢变化在第二种乳腺癌细胞系MDA-MB-231中得到证实。综上所述，我们的研究结果表明，PCho和乳酸盐可以作为无创代谢生物标志物，用于监测靶向PI3K/Akt通路的抑制剂的作用，而不依赖于导致HIF-1α抑制的步骤。
Activation of the PI3K/Akt pathway is associated with the development of numerous human cancers. Thus, many emerging therapies target this pathway. Previous studies have shown that targeting the PI3K/Akt pathway at the level of PI3K is associated with a drop in phosphocholine (PCho) and a reduction in hyperpolarized lactate production. However, the consequences of targeting downstream of PI3K at the level of Akt have not been investigated. Perifosine is an anticancer alkylphospholipid in clinical trials. It acts by inhibiting phosphorylation of Akt and was also shown to inhibit CTP:phosphocholine cytidyltransferase (CT). The goal of this study was to identify the MRS-detectable metabolic consequences of treatment with perifosine in MCF-7 breast cancer cells. We found that perifosine treatment led to a 51±5% drop in PCho from 30±5 fmol/cell to 15±1 fmol/cell and a comparable drop in de novo synthesized PCho. This was associated with a drop in choline kinase (ChoK) activity and ChoKα expression. CT inhibition could not be ruled out but likely did not contribute to the change in PCho. We also found that intracellular lactate levels decreased from 2.7±0.5 fmol/cell to 1.5±0.3 fmol/cell and extracellular lactate levels dropped by a similar extent. These findings were consistent with a drop in lactate dehydrogenase expression, and associated with a drop in activity of the hypoxia inducible factor (HIF)-1α. The drops in PCho and lactate production following perifosine treatment are therefore mediated downstream of Akt by the drop in HIF-1α, which serves as the transcription factor for both ChoK and lactate dehydrogenase. The metabolic changes were confirmed in a second breast cancer cell line, MDA-MB-231. Taken together, our findings indicate that PCho and lactate can serve as noninvasive metabolic biomarkers for monitoring the effects of inhibitors that target the PI3K/Akt pathway, independent of the step that leads to inhibition of HIF-1α.
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影响因子：
4.8
作者：
Chung, Yuen-Li;Troy, Helen;Beloueche-Babari, Mounia
通讯作者：
Beloueche-Babari, Mounia
影响因子：
5.7
作者：
Beloueche-Babari, M;Jackson, LE;Ronen, SM
通讯作者：
Ronen, SM
影响因子：
11.5
作者：
Hennessy, Bryan T.;Lu, Yiling;Mills, Gordon B.
通讯作者：
Mills, Gordon B.
影响因子：
11.2
作者：
Glunde, Kristine;Shah, Tariq;Bhujwalla, Zaver M.
通讯作者：
Bhujwalla, Zaver M.
影响因子：
11.2
作者：
Dafni H;Larson PE;Hu S;Yoshihara HA;Ward CS;Venkatesh HS;Wang C;Zhang X;Vigneron DB;Ronen SM
通讯作者：
Ronen SM