Quan Jing, Li Namei, Tan Yue, Liu Huiwen, Liao Weihua, Cao Ya, Luo Xiangjian
Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China; Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China.
Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
Life Sci. 2022 Jul 1;300:120558. doi: 10.1016/j.lfs.2022.120558. Epub 2022 Apr 19.
Cancer cells frequently undergo metabolic reprogramming, which contributes to tumorigenicity and malignancy. Unlike primary cancers, during the process of invasion and distal dissemination, cancer cells are deficient in ATP due to damaged glucose transport. Cells need to rewire metabolic programs to overcome nutrient and energy crises, maintaining survival and forming metastasis. However, the underlying mechanism has not been well understood. We elucidated the metabolic alteration in TGFβ1-induced epithelial-mesenchymal transition (EMT) and metastasis of nasopharyngeal carcinoma (NPC).
Fluorescent Bodipy fatty acid probe, UPLC-MS/MS analysis, β-oxidation assay, cellular ATP and NADPH/NADP measurement, and Oil Red-O staining were performed to evaluate the activation of FAO pathways in the TGFβ1-induced EMT of NPC cells. Three-dimensional (3D) invasion assay and metastatic animal model were applied to assess the invasive and metastatic capacity of NPC cells.
Our current findings reveal that PGC1α-mediated FAO promotes TGFβ1-induced EMT and metastasis of NPC cells. Mechanically, TGFβ1 up-regulates AMPKα1 to activate PGC1α, which transcriptionally boosts FAO-associated genes. The metabolic rewiring mediated by PGC1α facilitates EMT, invasion, and metastasis of NPC.
The present study aims to establish the mechanistic connection between energy metabolic reprogramming and the aggressive phenotype of NPC. These actions further provide new opportunities for developing of novel therapeutics for NPC by targeting PGC1α/ FAO signaling.
癌细胞经常发生代谢重编程，这有助于肿瘤发生和恶性发展。与原发性癌症不同，在侵袭和远处播散过程中，由于葡萄糖转运受损，癌细胞的三磷酸腺苷（ATP）缺乏。细胞需要重新调整代谢程序以克服营养和能量危机，维持生存并形成转移。然而，其潜在机制尚未完全清楚。我们阐明了转化生长因子β1（TGFβ1）诱导的鼻咽癌（NPC）上皮-间质转化（EMT）和转移过程中的代谢改变。
采用荧光Bodipy脂肪酸探针、超高效液相色谱-串联质谱（UPLC-MS/MS）分析、β-氧化测定、细胞ATP及烟酰胺腺嘌呤二核苷酸磷酸（NADPH）/烟酰胺腺嘌呤二核苷酸磷酸（NADP）测量以及油红O染色，以评估NPC细胞TGFβ1诱导的EMT过程中脂肪酸氧化（FAO）途径的激活情况。应用三维（3D）侵袭试验和转移动物模型评估NPC细胞的侵袭和转移能力。
我们目前的研究结果表明，过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）介导的FAO促进NPC细胞TGFβ1诱导的EMT和转移。机制上，TGFβ1上调腺苷酸活化蛋白激酶α1（AMPKα1）以激活PGC1α，后者转录增强FAO相关基因。PGC1α介导的代谢重编程促进NPC的EMT、侵袭和转移。
本研究旨在建立能量代谢重编程与NPC侵袭性表型之间的机制联系。这些作用进一步为通过靶向PGC1α/FAO信号通路开发NPC新型治疗方法提供了新机会。
