Rewiring carbohydrate catabolism differentially affects survival of pancreatic cancer cell lines with diverse metabolic profiles.
Rewiring carbohydrate catabolism differentially affects survival of pancreatic cancer cell lines with diverse metabolic profiles.
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DOI：
10.18632/oncotarget.17172
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发表时间：
2017-06-20
期刊：
影响因子：
--
通讯作者：
Piccoli C
中科院分区：
文献类型：
--
作者：
Tataranni T;Agriesti F;Ruggieri V;Mazzoccoli C;Simeon V;Laurenzana I;Scrima R;Pazienza V;Capitanio N;Piccoli C
越来越多的证据表明，靶向细胞代谢是治疗胰腺癌、克服化疗耐药性和改善患者预后和生存的一种有希望的有效方法。在这项研究中，在全基因组表达分析之后，我们选择了两种胰腺癌细胞系PANC-1和BXPC-3，其特征在于不同的代谢谱，特别关注碳水化合物代谢。功能比较分析显示，BXPC-3显示出线粒体呼吸和氧化磷酸化活性的显著缺陷，以及更高的活性氧物质产生和降低的NAD+/NADH比率，表明它们的生物能量依赖于糖酵解和与PANC-1相比不同的氧化还原稳态。两种细胞系都受到挑战，通过用半乳糖取代葡萄糖作为碳源来重新连接它们的代谢，这是一种抑制糖酵解通量并促进糖碳完全氧化的条件。所获得的数据惊人地显示，线粒体呼吸受损的BXPC-3细胞系不能维持葡萄糖剥夺/取代所需的代谢适应，从而导致G2\M细胞周期移位，氧化还原稳态失衡，凋亡诱导。相反，线粒体呼吸活性-PANC-1细胞系没有显示出明显的细胞耐受性证据。我们的研究结果提供了一个强有力的理由，候选代谢作为一个有前途的目标，癌症治疗。定义胰腺癌诊断时的代谢特征以及其他肿瘤的代谢特征，对于预测对影响代谢的治疗方法或辅助干预的反应性似乎至关重要。
An increasing body of evidence suggests that targeting cellular metabolism represents a promising effective approach to treat pancreatic cancer, overcome chemoresistance and ameliorate patient's prognosis and survival. In this study, following whole-genome expression analysis, we selected two pancreatic cancer cell lines, PANC-1 and BXPC-3, hallmarked by distinct metabolic profiles with specific concern to carbohydrate metabolism. Functional comparative analysis showed that BXPC-3 displayed a marked deficit of the mitochondrial respiratory and oxidative phosphorylation activity and a higher production of reactive oxygen species and a reduced NAD+/NADH ratio, indicating their bioenergetic reliance on glycolysis and a different redox homeostasis as compared to PANC-1. Both cell lines were challenged to rewire their metabolism by substituting glucose with galactose as carbon source, a condition inhibiting the glycolytic flux and fostering full oxidation of the sugar carbons. The obtained data strikingly show that the mitochondrial respiration-impaired-BXPC-3 cell line was unable to sustain the metabolic adaptation required by glucose deprivation/substitution, thereby resulting in a G2\M cell cycle shift, unbalance of the redox homeostasis, apoptosis induction. Conversely, the mitochondrial respiration-competent-PANC-1 cell line did not show clear evidence of cell sufferance. Our findings provide a strong rationale to candidate metabolism as a promising target for cancer therapy. Defining the metabolic features at time of pancreatic cancer diagnosis and likely of other tumors, appears to be crucial to predict the responsiveness to therapeutic approaches or coadjuvant interventions affecting metabolism.
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影响因子：
29
作者：
Pavlova NN;Thompson CB
通讯作者：
Thompson CB
影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
影响因子：
4.4
作者：
Cela, Olga;Piccoli, Claudia;Capitanio, Nazzareno
通讯作者：
Capitanio, Nazzareno
DOI：
10.1073/pnas.1501605112
发表时间：
2015-08-11
影响因子：
11.1
作者：
Daemen, Anneleen;Peterson, David;Evangelista, Marie
通讯作者：
Evangelista, Marie
影响因子：
7.3
作者：
Galli, Ubaldina;Travelli, Cristina;Genazzani, Armando A.
通讯作者：
Genazzani, Armando A.