ALDH1A3 Accelerates Pancreatic Cancer Metastasis by Promoting Glucose Metabolism

Abstract

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 ALDH1A3 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-PPARγ (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 PPARγ 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. PPARγ and its downstream PI3K/AKT/mTOR signaling pathway maybe involved in this process.

Identification of a novel glycolysis-related gene signature for predicting the prognosis of osteosarcoma patients

“…Feng et al illustrated that aerobic glycolysis could promote the growth and metastasis of hepatocellular carcinoma [ 38 ]. In pancreatic cancer, Nie et al found that ALDH1A3 promoted the metastasis of tumor cells by enhancing the glycolysis in them [ 39 ]. In our study, we divided the patients into high- and low-risk groups according to an established risk signature.…”

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

“…These results suggest that the pro-proliferation and anti-apoptotic functions of KLK8 may not be dependent on activation of Notch signaling pathway. Notably, our GSEA analysis data showed that KLK8 overexpression might also lead to the activation of EMT (epithelial-mesenchymal transition), glycolysis and KRAS signaling pathway, which have been implicated in the pathogenesis and progression of pancreatic cancers (17,(55)(56)(57). Whether these processes and the related signaling pathways contribute to the KLK8-induced pro-proliferation and antiapoptotic effects in pancreatic cancers merits further investigation.…”

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

“…These results suggest that the proproliferation and anti-apoptotic functions of KLK8 may not be dependent on activation of Notch signaling pathway. Notably, our GSEA analysis data showed that KLK8 overexpression might also lead to the activation of EMT (epithelial-mesenchymal transition), glycolysis and KRAS signaling pathway, which have been implicated in the pathogenesis and progression of pancreatic cancers [17,[43][44][45]. Whether these processes and the related signaling pathways contribute to the KLK8-induced pro-proliferation and anti-apoptotic effects in pancreatic cancers merits further investigation.…”

“…Staining intensity was scored as follows [16]: 0 = no color; 1 = yellow; 2 = light brown; and 3 = dark brown. The proportion of immune-positive tumor cells (number of positively labeled tumor cells / number of total tumor cells) was scored as follows [17]: 0, positive cells < 5%; 1, 6%-25% positive cells;2, 26%-50% positive cells; 3, positive cells 51%-75%; and 4 > 76%. ).…”