# Oxidative pentose phosphate pathway regulates AMPK homeostasis by balancing opposing LKB1 and PP2A

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $386,416

## Abstract

Project Summary/Abstract:
The interplay between metabolic pathways and cell signaling networks that contribute to the “metabolic
reprogramming” in cancer cells remains largely unknown. The oxidative pentose phosphate pathway (oxiPPP)
plays a crucial role in the metabolic coordination of glycolysis, biosynthesis and redox homeostasis in cells by
producing precursors for nucleotide and lipid biosynthesis, as well as antioxidant NADPH that quenches the
reactive oxygen species (ROS) produced during rapid proliferation of cancer cells. There are three key enzymes
along the oxiPPP. The first enzyme glucose-6-phosphate dehydrogenase (G6PD) converts glycolytic
intermediate glucose-6-phosphate (G6P) to 6-phosphogluconolactone (6PGL) and produces NADPH. The
second enzyme 6-phosphogluconolactonase (PGLS) converts 6PGL to 6-phosphogluconate (6PG). The third
enzyme 6-phosphogluconate dehydrogenase (6PGD) converts 6PG to ribulose-5-phosphate (Ru-5-P) and also
produces NADPH. We recently reported that 6PGD is commonly activated by lysine acetylation in cancer cells
and activates lipogenesis through controlling its product Ru-5-P, which inhibits the LKB1-AMPK pathway by
disrupting the active LKB1 complex (Shan et al., 2014 Mol Cell; Lin et al., 2015, Nat Cell Biol.). Interestingly, we
found that knockdown of G6PD did not alter AMPK activation despite decreased Ru-5-P and subsequent LKB1
activation, due to enhanced activity of PP2A, the upstream phosphatase of AMPK. In contrast, knockdown of
6PGD or PGLS reduced PP2A activity. Mechanistically, knockdown of G6PD or PGLS decreased or increased
6PGL level, respectively, which enhanced the inhibitory phosphorylation of PP2A by Src. There are two forms of
6PGL, γ-6-phosphogluconolactone (γ-6PGL) is an oxiPPP byproduct with unknown function that is generated
through intramolecular rearrangement of δ-6-phosphogluconolactone (δ-6GL), while δ-6PGL is the only
substrate of PGLS and can undergo quick spontaneous hydrolysis. Thus, γ-6PGL is relatively stable compared
to δ-6GL but does not participate in oxiPPP. Further studies revealed that γ-6PGL, but not δ-6GL, promotes
Src-PP2A association, probably by binding to Src but not PP2A and enhancing PP2A recruitment.
 Thus, we hypothesize that G6PD, PGLS and 6PGD play differential roles in regulation of AMPK
homeostasis by balancing the opposing LKB1 and PP2A, through the oxiPPP intermediate Ru-5-P and an
oxiPPP “byproduct” γ-6PGL, respectively; and γ-6PGL, previously considered as a “dead end” byproduct of the
oxiPPP with unknown physiological function, functions as a signaling molecule that links the metabolic oxiPPP
with the Src-PP2A-AMPK signaling pathway. The specific aims are proposed: (1) To elucidate the molecular and
signaling basis underlying γ-6PGL-dependent contribution to AMPK activation through inhibition of PP2A by Src;
(2) To determine the differential effects of G6PD and PGLS on AMPK activation, redox homeostasis and tumor
growth; and (3) To evaluate combined t...

## Key facts

- **NIH application ID:** 10140303
- **Project number:** 5R01CA174786-08
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Jing Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $386,416
- **Award type:** 5
- **Project period:** 2014-04-15 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10140303

## Citation

> US National Institutes of Health, RePORTER application 10140303, Oxidative pentose phosphate pathway regulates AMPK homeostasis by balancing opposing LKB1 and PP2A (5R01CA174786-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10140303. Licensed CC0.

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