# Examining Biosynthesis and NAD+ Demand in the Warburg Effect

> **NIH NIH F31** · DUKE UNIVERSITY · 2020 · $37,055

## Abstract

Abstract
Cancer cells frequently reprogram metabolism to support increased proliferation, and cancer therapies that target
these metabolic demands have been used frequently clinically and show continued promise as new therapeutics.
The increased uptake of glucose and its extensive conversion to lactate is the most notable metabolic alteration
of cancer cells, and this phenomenon has been termed the ‘Warburg Effect’. During Warburg Effect, significant
amounts of glucose are seemingly wasted due to its conversion to lactate, as much of the lactate is excreted
from the cell instead of the carbon being used as a biosynthetic building block to produce the molecules required
for cell growth and proliferation. However, it is unknown whether the Warburg Effect actually limits cellular
biosynthetic capacity, and it is commonly proposed that the Warburg Effect functions to promote a net increase
in biosynthesis and thus proliferation. Our lab has recently developed a mathematical model of Warburg Effect,
which indicates that Warburg Effect arises to help meet NAD+ demand. The model predicts that Warburg Effect
promotes a relatively small increase in biosynthesis by relieving limited NAD+ levels, but further increases in
biosynthesis and proliferation entail decreased Warburg Effect. In this proposal, I aim to test the predictions of
this model and to thoroughly interrogate the relationship between the Warburg Effect, NAD+ demand, and
glucose usage in biosynthesis. To do this, I will first manipulate NAD+ levels using two independent methods in
a panel of primary and established cancer cell lines and quantitatively determine whether each cell line
decreases its use of the Warburg Effect (Aim I). I will then measure glucose flux into multiple biosynthetic
pathways in this panel of cancer cell lines at baseline and during NAD+ modulation, and determine whether the
flux of glucose into nucleotide biosynthesis and proliferation is related to the extent of Warburg Effect displayed
by each cell line (Aim II). I will extend Aim II by examining whether KA, a drug that selectively disrupts the
Warburg Effect, disrupts glucose flux into nucleotide biosynthetic intermediates in a genetically engineered soft-
tissue sarcoma mouse model. In cell culture I will determine whether increasing NAD+ levels can rescue this
metabolic disruption, as would be predicted by our lab’s model. The proposed work builds upon recent advances
our lab has made in understanding the Warburg Effect and will further the collective understanding of how this
metabolic phenomenon arises and impacts biosynthesis, a process absolutely necessary for the sustained
proliferation of cancer cells. Furthermore, it will determine whether the Warburg Effect imposes biosynthetic
vulnerabilities upon cancer cells and help define contexts in which targeting the Warburg Effect will be useful as
a cancer therapy.

## Key facts

- **NIH application ID:** 9898145
- **Project number:** 5F31CA232658-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Annamarie Elizabeth Allen
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,055
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898145

## Citation

> US National Institutes of Health, RePORTER application 9898145, Examining Biosynthesis and NAD+ Demand in the Warburg Effect (5F31CA232658-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898145. Licensed CC0.

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