# HHEX-PRKAR2B axis-mediated PKA activation drives glucose metabolism-dependent progression of pancreatic ductal adenocarcinoma

## 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.

## Key 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 promote metastasis, whereas glycolysis inhibition blocked new metastases. Thus, HHEX-PRKAR2B-mediated PKA activation is a critical hub for PDAC progression, modulated by glucose and reinforcing glycolysis via HK2, revealing novel therapeutic targets for metabolic intervention.

•The HHEX-PRKAR2B-PKA-glycolysis metabolic-signaling axis drives PDAC progression•PRKAR2B suppression and cAMP elevation sustain PKA activation in PDAC•PKA activity is a potential biomarker for PDAC differentiation grade and poor prognosis•PRKAR2B enables targeted suppression of PDAC progression as a promising therapeutic target

The HHEX-PRKAR2B-PKA-glycolysis metabolic-signaling axis drives PDAC progression

PRKAR2B suppression and cAMP elevation sustain PKA activation in PDAC

PKA activity is a potential biomarker for PDAC differentiation grade and poor prognosis

PRKAR2B enables targeted suppression of PDAC progression as a promising therapeutic target

Human metabolism; Molecular interaction; Cancer