Liu Menghan, Quek Lake-Ee, Sultani Ghazal, Turner Nigel
Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW Australia.
Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, NSW Australia ; Charles Perkins Centre, School of Mathematics and Statistics, The University of Sydney, Sydney, NSW 2006 Australia.
Cancer Metab. 2016 Oct 17;4:19. doi: 10.1186/s40170-016-0160-x. eCollection 2016.
Pancreatic ductal adenocarcinoma (PDAC) is a common malignancy with dismal prognosis. Metastatic spread and therapeutic resistance, the main causes of PDAC-related mortalities, are both partially underlined by the epithelial-mesenchymal transition (EMT) of PDAC cells. While the role of Warburg metabolism has been recognized in supporting rapid cellular growth and proliferation in many cancer types, less is known about the metabolic changes occurring during EMT, particularly in the context of PDAC.
In the current study, experimental models of EMT were established in the Panc-1 cell line of human PDAC via exposure to two physiologically relevant EMT inducers (tumor necrosis factor-α and transforming growth factor-β) and the metabolic consequences examined. The two EMT models displayed similar alterations in the general metabolic profile including augmented glucose uptake and lactate secretion as well as the lack of change in oxidative metabolism. Examination of molecular markers revealed differences in the pathways underlying the metabolic rewiring. C-Glucose tracer data confirmed that a major portion of accumulated lactate was derived from glucose, but subsequent flux analysis suggested involvement of non-canonical pathways towards lactate production.
Our results characterize the metabolic reprogramming occurring during PDAC cell EMT and highlight the common changes of increased glucose uptake and lactate secretion under different EMT conditions. Such insight is urgently required for designing metabolic strategies to selectively target cells undergoing EMT in PDAC.
胰腺导管腺癌（PDAC）是一种常见的恶性肿瘤，预后较差。转移扩散和治疗耐药是PDAC相关死亡的主要原因，二者均部分归因于PDAC细胞的上皮-间质转化（EMT）。虽然瓦伯格代谢在支持多种癌症类型的快速细胞生长和增殖中的作用已得到认可，但对于EMT过程中发生的代谢变化，尤其是在PDAC背景下，人们了解较少。
在本研究中，通过暴露于两种生理相关的EMT诱导剂（肿瘤坏死因子-α和转化生长因子-β），在人PDAC的Panc-1细胞系中建立了EMT实验模型，并检测了代谢后果。这两种EMT模型在一般代谢谱中表现出相似的改变，包括葡萄糖摄取增加和乳酸分泌增加，以及氧化代谢无变化。分子标志物检测揭示了代谢重编程潜在途径的差异。¹³C-葡萄糖示踪数据证实，积累的乳酸大部分来自葡萄糖，但随后的通量分析表明非经典途径参与了乳酸生成。
我们的结果描述了PDAC细胞EMT过程中发生的代谢重编程，并突出了不同EMT条件下葡萄糖摄取增加和乳酸分泌增加的共同变化。对于设计代谢策略以选择性靶向PDAC中经历EMT的细胞而言，这种见解迫切需要。
