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Updated: Mar 7, 2026

Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture
08:16

Mimicking and Manipulating Pancreatic Acinar-to-Ductal Metaplasia in 3-dimensional Cell Culture

Published on: February 11, 2019

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Mutant Kras- and p16-regulated NOX4 activation overcomes metabolic checkpoints in development of pancreatic ductal

Huai-Qiang Ju1,2, Haoqiang Ying2, Tian Tian1

  • 1Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.

Nature Communications
|February 25, 2017
PubMed

Insights

Pancreatic cancer (PDAC) development involves Kras activation and p16 inactivation. We found NAD(P)H oxidase 4 (NOX4) links these, promoting PDAC cell growth by boosting glycolysis, suggesting NOX4 as a therapeutic target.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) development requires both Kras activation and p16 inactivation.
  • The precise biochemical mechanisms connecting these critical alterations in PDAC remain incompletely understood.

Purpose of the Study:

  • To elucidate the biochemical link between p16 inactivation and Kras activation in PDAC.
  • To identify novel molecular players and pathways involved in PDAC pathogenesis.

Main Methods:

  • Gene expression profiling studies to identify upregulated enzymes upon p16 inactivation.
  • Analysis of NOX4 activity, p22phox expression, and metabolic pathways in PDAC cell lines and patient specimens.
  • Investigating the regulatory mechanisms of NOX4 and p22phox induction.

Main Results:

  • NAD(P)H oxidase 4 (NOX4) is upregulated following p16 inactivation.
  • Kras activation leads to increased p22phox, a component required for NOX4 activation.
  • Elevated NOX4 activity enhances NADH oxidation, increases NAD+ availability, and promotes glycolysis, thereby supporting PDAC cell proliferation.
  • NOX4 induction is regulated by p16-Rb-E2F signaling, while p22phox is induced by KrasG12V-NF-κB signaling.

Conclusions:

  • This study reveals a biochemical mechanism explaining the synergistic roles of p16 inactivation and Kras activation in PDAC.
  • NOX4 acts as a crucial mediator, linking these genetic alterations to metabolic reprogramming and tumor growth.
  • NOX4 represents a promising therapeutic target for pancreatic ductal adenocarcinoma.

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