ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism
ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism
复制标题
ALDH1A3 通过促进葡萄糖代谢加速胰腺癌转移
DOI：
10.3389/fonc.2020.00915
复制
发表时间：
2020-06-16
影响因子：
4.7
通讯作者：
Shen, Shanshan
中科院分区：
文献类型：
--
作者：
Nie, Shuang;Qian, Xuetian;Shen, Shanshan
背景：乙醛脱氢酶 1 家族成员 A3 (ALDH1A3) 是与多种代谢过程（包括葡萄糖代谢）相关的关键酶。我们最近发现葡萄糖代谢在促进胰腺导管腺癌（PDAC）的转移中发挥着重要作用。由于ALDH1 A3标记了PDAC的侵袭性亚型，我们假设ALDH1A3通过其对葡萄糖代谢的代谢作用促进PDAC转移。方法：通过免疫组织化学检测人PDAC组织中ALDH1A3的表达。 shRNA 或过表达载体在 PDAC 细胞中敲低或过表达 ALDH1A3。 ALDH1A3 的功能作用在体外和体内进行了表征。通过 RNA 测序进行转录分析用于探索可能的潜在分子机制。测量葡萄糖摄取、细胞外乳酸和 ATP 产生，以了解 ALDH1A3 对 PDAC 细胞的代谢影响。结果：ALDH1A3 与 PDAC 患者的不良预后相关。在功能上，ALDH1A3 在体外和体内促进 PDAC 转移。进一步研究发现，ALDH1A3激活PI3K/AKT/mTOR信号通路及其下游靶点PPARγ（过氧化物酶体增殖物激活受体γ）。这导致 HK2（己糖激酶 2）的表达增加，随后增强了 PDAC 细胞中的糖酵解。此外，药理学抑制 ALDH1A3 阳性细胞中 PPAR gamma 活性会损害糖酵解基因表达、PI3K/AKT/mTOR 活性和细胞糖酵解。结论：ALDH1A3 通过其对葡萄糖代谢的代谢影响促进 PDAC 转移。 PPAR gamma及其下游PI3K/AKT/mTOR信号通路可能参与了这一过程。
Background: The aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is a key enzyme associated with a variety of metabolic processes, including glucose metabolism. We recently uncovered that glucose metabolism played an essential role in promoting metastasis of pancreatic ductal adenocarcinoma (PDAC). As ALDH1 A3 labels an aggressive subtype of PDAC, we hypothesized that ALDH1A3 functionally promoted PDAC metastasis via its metabolic effect on glucose metabolism.Methods: Expression of ALDH1A3 was detected in human PDAC tissues by immunohistochemistry. ALDH1A3 was knocked down or overexpressed in PDAC cells by either shRNA or overexpression vector. The functional roles of ALDH1A3 were characterized in vitro and in vivo. Transcriptional profiling via RNA-sequencing was used to explore the possible underlying molecular mechanisms. Glucose uptake, extracellular lactate, and ATP production were measured to access the metabolic influence of ALDH1A3 on PDAC cells.Results: ALDH1A3 was associated with poor prognosis in PDAC patients. Functionally, ALDH1A3 promoted PDAC metastasis in vitro and in vivo. Further studies revealed that ALDH1A3 activated PI3K/AKT/mTOR signaling pathway and its downstream target-PPAR gamma (peroxisome proliferator-activated receptor gamma). This led to increase the expression of HK2 (hexokinase 2), which subsequently enhanced the glycolysis in PDAC cells. Additionally, the pharmacological inhibition of PPAR gamma activity in ALDH1A3-positive cells impaired glycolytic genes expression, PI3K/AKT/mTOR activity and cellular glycolysis.Conclusions: ALDH1A3 promotes PDAC metastasis via its metabolic influence on glucose metabolism. PPAR gamma and its downstream PI3K/AKT/mTOR signaling pathway maybe involved in this process.