Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin.
Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin.
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近年来，靶向肿瘤特异性代谢作为一种有前途的治疗策略已经引起了人们的兴趣。我们发现线粒体酶琥珀酸脱氢酶（SDHA）的过度表达在卵巢癌患者中非常普遍，并有助于卵巢肿瘤模型中线粒体代谢的升高。SDHA过表达的肿瘤细胞是高度代谢活性的，依赖于线粒体中的糖酵解和氧化磷酸化来满足其能量需求。此外，我们发现这些细胞特别容易受到葡萄糖和谷氨酰胺等必需营养素的剥夺，这导致ATP产量大幅减少。最后，我们鉴定了一种抗代谢化合物紫草素，其对SDHA过表达的卵巢癌细胞表现出有效的抗肿瘤功效。总的来说，我们努力通过揭示SDHA在卵巢癌代谢重编程中以前未被认识到的作用来推进科学知识，这为治疗干预提供了未开发的机会。我们发现线粒体酶琥珀酸脱氢酶（SDHA）的过度表达在卵巢癌中特别普遍，并促进高代谢活性表型。此前曾在一些罕见疾病中研究过琥珀酸脱氢酶缺乏症。然而，SDHA上调的作用及其对卵巢癌代谢的影响从未被研究过，强调需要进一步研究。我们研究了卵巢癌中SDHA过表达的功能后果。使用蛋白质组学方法和生物测定，我们询问蛋白质含量的代谢途径，细胞增殖，锚定非依赖性生长，线粒体呼吸，糖酵解功能，和ATP生产率在这些细胞。最后，我们进行了药物筛选，以确定特异性靶向SDHA过表达肿瘤细胞的药物。我们发现，SDHA过表达细胞的特征在于增强的能量代谢，依赖于糖酵解和氧化磷酸化来满足其能量需求。此外，SDHA-高表型与细胞对葡萄糖和谷氨酰胺剥夺的脆弱性相关，这导致ATP产量的大幅降低。我们还鉴定了一种抗代谢化合物紫草素，其对SDHA过表达的卵巢癌细胞具有强效功效。我们的数据强调了SDHA在卵巢癌代谢重编程中未被重视的作用，这代表了治疗干预的新机会。
In recent years, targeting tumor specific metabolism has gained an interest as a promising therapeutic strategy. We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is highly prevalent in ovarian carcinoma patients and contributes to elevated mitochondrial metabolism in ovarian tumor models. The SDHA overexpressing tumor cells are highly metabolically active, relying on both glycolysis and oxidative phosphorylation in mitochondria to meet their energy requirements. Further, we found that those cells are particularly vulnerable to deprivation of essential nutrients such as glucose and glutamine, which led to a substantial reduction of ATP yield. Lastly, we identified an anti-metabolic compound shikonin, which demonstrated a potent anti-tumor efficacy against SDHA overexpressing ovarian cancer cells. Overall, we strive to advance scientific knowledge by uncovering the previously unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which holds untapped opportunities for therapeutic intervention. We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention.
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影响因子：
8.8
作者：
Cheng, G.;Zielonka, J.;McAllister, D.;Tsai, S.;Dwinell, M. B.;Kalyanaraman, B.
通讯作者：
Kalyanaraman, B.
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Rattan R
影响因子：
2
作者：
Courage, Carolina;Jackson, Christopher B.;Schaller, Andre
通讯作者：
Schaller, Andre
影响因子：
3.7
作者：
Anderson AS;Roberts PC;Frisard MI;Hulver MW;Schmelz EM
通讯作者：
Schmelz EM
影响因子：
3.7
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.
通讯作者：
Schmelz, Eva M.