HHEX-PRKAR2B axis-mediated PKA activation drives glucose metabolism-dependent progression of pancreatic ductal adenocarcinoma
Junxiang Wen, Qiuchen Li, Shuxiang Xu, Wenjun Lu, Fei Wu, Jiatao Lou, Lin Wang
TL;DR
The study reveals that a specific signaling pathway involving HHEX and PRKAR2B drives the progression of pancreatic cancer by boosting glucose metabolism.
Contribution
The study identifies a novel HHEX-PRKAR2B-PKA-glycolysis axis as a key driver of pancreatic cancer progression.
Findings
Aberrant PKA activation in pancreatic cancer correlates with poor prognosis.
High glucose environments enhance PKA activity and glycolysis via HK2 upregulation.
Inhibiting glycolysis blocks metastasis in high-glucose conditions.
Abstract
By virtue of its function as a key metabolic regulator, malignant transformation in the pancreas not only confers high aggressiveness but also disrupts systemic metabolism. However, the causal relationship between metabolic reprogramming and the progression of pancreatic ductal adenocarcinoma (PDAC) remains incompletely understood. This study identifies aberrant protein kinase A (PKA) activation in PDAC, correlating with poor prognosis. Mechanistically, downregulation of the transcription factor hematopoietically expressed homeobox (HHEX) represses protein kinase cAMP-dependent type II regulatory subunit beta (PRKAR2B), relieving inhibition on PKA catalytic activity. A high-glucose microenvironment promotes cAMP production, further activating PKA, which then enhances glycolysis via specific upregulation of hexokinase 2 (HK2). In vivo, high glucose synergized with PKA activation to…
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Taxonomy
TopicsCancer, Hypoxia, and Metabolism · Pancreatic function and diabetes · Metabolism, Diabetes, and Cancer