Terlizzi Michela, Molino Antonio, Colarusso Chiara, Somma Pasquale, De Rosa Ilaria, Troisi Jacopo, Scala Giovanni, Salvi Rosario, Pinto Aldo, Sorrentino Rosalinda
Department of Pharmacy, DIFARMA, University of Salerno, Fisciano, Salerno, Italy.
ImmunePharma S.r.l., Salerno, Italy.
Oncotarget. 2020 Sep 22;11(38):3515-3525. doi: 10.18632/oncotarget.27724.
Lung cancer is by far the leading cause of cancer death. Metabolomic studies have highlighted that both tumor progression and limited curative treatment options are partly due to dysregulated glucose metabolism and its associated signaling pathways. In our previous studies, we identified caspase-4 as a novel diagnostic tool for non-small cell lung cancer (NSCLC). Here, we analyzed the metabolomic profile of both plasma and tumor tissues of NSCLC patients stratified as caspase-4 positive or negative. We found that circulating caspase-4 was correlated to LDH. However, this effect was not observed in caspase-4 positive tumor tissues, where instead, fatty acid biosynthesis was favoured in that the malonic acid and the palmitic acid were higher than in non-cancerous and caspase-4 negative tissues. The glycolytic pathway in caspase-4 positive NSCLC tissues was bypassed by the malonic acid-dependent lipogenesis. On the other hand, the dysregulated glucose metabolism was regulated by a higher presence of succinate dehydrogenase (SDHA) and by the gluconeogenic valine which favoured Krebs' cycle. In conclusion, we found that the recently identified caspase-4 positive subpopulation of NSCLC patients is characterized by a lipidomic profile accompanied by alternative pathways to guarantee glucose metabolism in favour of tumor cell proliferation.
肺癌是目前癌症死亡的主要原因。代谢组学研究表明，肿瘤进展和有限的治疗选择部分归因于葡萄糖代谢失调及其相关信号通路。在我们之前的研究中，我们将半胱天冬酶-4鉴定为非小细胞肺癌（NSCLC）的一种新型诊断工具。在此，我们分析了根据半胱天冬酶-4阳性或阴性分层的NSCLC患者血浆和肿瘤组织的代谢组学特征。我们发现循环中的半胱天冬酶-4与乳酸脱氢酶相关。然而，在半胱天冬酶-4阳性肿瘤组织中未观察到这种效应，相反，在半胱天冬酶-4阳性肿瘤组织中脂肪酸生物合成占优势，因为丙二酸和棕榈酸高于非癌组织和半胱天冬酶-4阴性组织。丙二酸依赖性脂肪生成绕过了半胱天冬酶-4阳性NSCLC组织中的糖酵解途径。另一方面，琥珀酸脱氢酶（SDHA）的较高表达以及有利于三羧酸循环的糖异生缬氨酸调节了失调的葡萄糖代谢。总之，我们发现最近鉴定出的NSCLC患者半胱天冬酶-4阳性亚群的特征是脂质组学特征，伴有替代途径以保证有利于肿瘤细胞增殖的葡萄糖代谢。
