Metabolic changes during ovarian cancer progression as targets for sphingosine treatment.
Metabolic changes during ovarian cancer progression as targets for sphingosine treatment.
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DOI：
10.1016/j.yexcr.2013.02.017
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发表时间：
2013-06-10
影响因子：
3.7
通讯作者：
Schmelz, Eva M.
中科院分区：
文献类型：
--
作者：
Anderson, Angela S.;Roberts, Paul C.;Frisard, Madlyn I.;McMillan, Ryan P.;Brown, Timothy J.;Lawless, Michael H.;Hulver, Matthew W.;Schmelz, Eva M.
肿瘤细胞通常表现出改变的代谢表型。然而，目前尚不清楚这种转变何时发生在卵巢癌中，以及这些变化在临床预防和干预试验中作为治疗靶点的潜力。我们使用我们最近开发和表征的小鼠卵巢表面上皮（MOSE）癌症进展模型来研究不同疾病阶段的代谢变化。随着卵巢癌的进展，葡萄糖和脂肪酸的完全氧化显着减少，同时增加乳酸排泄和3 H-脱氧葡萄糖摄取的晚期癌细胞，转向更多的糖酵解表型的细胞。这些变化伴随着TCA通量的减少，但柠檬酸合酶活性的增加，为从头脂肪酸和胆固醇合成提供底物。此外，随着癌症的进展，线粒体中的解偶联最大呼吸速率降低。用1.5μM鞘氨醇（一种生物活性鞘脂代谢物）处理MOSE细胞，可降低柠檬酸合酶活性，增加TCA通量，降低胆固醇合成和糖酵解。总之，我们的数据证实了卵巢癌进展期间的代谢变化，表明这些变化的阶段特异性，并表明细胞代谢中的多个事件是外源性鞘氨醇的靶向，这可能对未来的预防试验至关重要。
Tumor cells often exhibit an altered metabolic phenotype. However, it is unclear as to when this switch takes place in ovarian cancer, and the potential for these changes to serve as therapeutic targets in clinical prevention and intervention trials. We used our recently developed and characterized mouse ovarian surface epithelial (MOSE) cancer progression model to study metabolic changes in distinct disease stages. As ovarian cancer progresses, complete oxidation of glucose and fatty acids were significantly decreased, concurrent with increases in lactate excretion and 3H-deoxyglucose uptake by the late-stage cancer cells, shifting the cells towards a more glycolytic phenotype. These changes were accompanied by decreases in TCA flux but an increase in citrate synthase activity, providing substrates for de novo fatty acid and cholesterol synthesis. Also, uncoupled maximal respiration rates in mitochondria decreased as cancer progressed. Treatment of the MOSE cells with 1.5μM sphingosine, a bioactive sphingolipid metabolite, decreased citrate synthase activity, increased TCA flux, decreased cholesterol synthesis and glycolysis. Together, our data confirm metabolic changes during ovarian cancer progression, indicate a stage specificity of these changes, and suggest that multiple events in cellular metabolism are targeted by exogenous sphingosine which may be critical for future prevention trials.
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影响因子：
7.4
作者：
Gerencser, Akos A.;Neilson, Andy;Choi, Sung W.;Edman, Ursula;Yadava, Nagendra;Oh, Richard J.;Ferrick, David A.;Nicholls, David G.;Brand, Martin D.
通讯作者：
Brand, Martin D.
影响因子：
5.6
作者：
Mazzei, Joseph C.;Zhou, Hui;Brayfield, Bradley P.;Hontecillas, Raquel;Bassaganya-Riera, Josep;Schmelz, Eva M.
通讯作者：
Schmelz, Eva M.
影响因子：
11.2
作者：
Migita, Toshiro;Narita, Tadahito;Ishikawa, Yuichi
通讯作者：
Ishikawa, Yuichi
影响因子：
5.6
作者：
Chang, HC;Tsai, LH;Hung, WC
通讯作者：
Hung, WC
DOI：
10.1038/oby.2005.61
发表时间：
2005-03-01
期刊：
OBESITY RESEARCH
影响因子：
--
作者：
Heilbronn, LK;Civitarese, AE;Ravussin, E
通讯作者：
Ravussin, E