Background:Ovarian cancer is the deadliest of all gynecologic malignancies due to limited therapeutic options. Our data show that the tumor-specific metabolism of ovarian cancer could be effectively targetable, which highlights a path for new anti-cancer therapies.Methods and Results:Our work shows that the upregulation of mitochondrial enzyme SDHA is particularly prevalent in ovarian carcinoma. SDHA overexpression significantly induced orthotopic ovarian tumor growth, reducing mouse survival. We showed that SDHA-overexpressing tumors depend on glutaminolysis and increased activity of the tricarboxylic acid (TCA) cycle coupled with mitochondrial oxidative phosphorylation (OXPHOS), which are essential for high-energy metabolism and cell survival. We identified a distinctive vulnerability of SDHA-overexpressing tumors to agents targeting regulators of the OXPHOS pathway, particularly the LRPPRC protein. LRPPRC is a key regulator of mitochondrial energy metabolism, promoting OXPHOS and ATP generation. However, when overexpressed, the LRPPRC acts as a tumor oncogene. Our analysis of SDHA and LRPPRC gene and protein expression patterns in precursor lesions and established ovarian cancer demonstrated that the upregulation of SDHA is accompanied by LRPPRC overexpression, notably in advanced tumors. Our novel findings highlight for the first time a potential functional interaction between SDHA and LRPPRC in the development and progression of ovarian malignancy. Importantly, our in vivo data showed that pharmacological inhibition of LRPPRC results in a lasting therapeutic benefit and can be an effective therapy in SDHA- and LRPPRC-overexpressing ovarian tumors.Conclusions:Overall, our study underlines an understudied role of concomitant overexpression of SDHA and LRPPRC in ovarian cancer pathogenesis, highlighting new paths for therapeutic development.
背景：卵巢癌因治疗手段有限，是所有妇科恶性肿瘤中致死率最高的癌症。我们的数据显示，卵巢癌的肿瘤特异性代谢过程具有可靶向性，这为新型抗癌疗法指明了方向。 方法与结果：研究发现线粒体酶SDHA的上调在卵巢癌中尤为普遍。SDHA过表达显著诱导原位卵巢肿瘤生长，降低小鼠存活率。我们证实SDHA过表达肿瘤依赖于谷氨酰胺分解及增强的三羧酸循环活性，并与线粒体氧化磷酸化过程相耦联，这些机制对高能量代谢和细胞存活至关重要。我们发现了SDHA过表达肿瘤对靶向氧化磷酸化通路调节因子（特别是LRPPRC蛋白）的药物具有独特敏感性。LRPPRC是线粒体能量代谢的关键调节因子，能促进氧化磷酸化和ATP生成。然而当其过表达时，LRPPRC会发挥肿瘤癌基因的作用。通过对癌前病变和确诊卵巢癌中SDHA与LRPPRC基因及蛋白表达模式的分析，我们发现SDHA上调伴随LRPPRC过表达，在晚期肿瘤中尤为显著。这一新发现首次揭示了SDHA与LRPPRC在卵巢恶性肿瘤发生发展过程中潜在的功能性相互作用。重要的是，体内实验数据显示，LRPPRC的药理学抑制能产生持续治疗效果，可能成为SDHA和LRPPRC过表达卵巢肿瘤的有效疗法。 结论：本研究系统阐明了SDHA与LRPPRC协同过表达在卵巢癌发病机制中尚未被充分认识的作用，为治疗开发提供了新方向。
肿瘤(癌症)患者之家