# Delineating how retinoic acids regulate lipid metabolism in glioblastoma and their resistance mechanisms

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $440,840

## Abstract

ABSTRACT
Glioblastoma (GBM) is the most common primary brain tumor and one of the most lethal of all cancers. The main
challenge in treating GBM is the quickly developing resistance to all kinds of treatments by tumor cells. Whereas
our partial understanding of GBM biology is a major roadblock to elucidate the underlying resistance
mechanisms. Our laboratory recently uncovered that GBM greatly alters lipid metabolism to gain sufficient lipids
for its rapid growth. We identified that sterol regulatory element-binding protein-1 (SREBP-1), a master
transcription factor that controls fatty acid synthesis, is highly expressed in GBM and is essential for tumor
growth. Our findings were recently validated by multiple groups showing that SREBP-1 is also elevated in various
other cancers. However, whether the dramatically altered lipid metabolism facilitates tumor resistance is
completely unknown. Moreover, the mechanism that upregulates SREBP-1 expression in cancer cells remains
elusive. Interestingly, we recently found that all-trans retinoic acid (ATRA) and 13-cis-RA could significantly
reduce the expression of SREBP-1 and lipogenic enzymes in a dose-dependent manner in GBM cells. These
retinoic acids are effective drugs in treating acute promyelocytic leukemia and have also been used to treat GBM
and other solid tumors, but tumor resistance has been very challenging. To date, both their antitumor and
resistance mechanisms remain poorly understood. We examined the expression of their binding partner, retinoic
acid nuclear receptor α (RARα) in GBM patient tissues and found it to be highly expressed in tumor tissues and
positively correlated with SREBP-1 expression, while inversely associated with poor patient survival.
Interestingly, our data further show that 13-cis-RA and ATRA treatment significantly increased the expression of
carnitine palmitoyltransferase 1A (CPT1A), a key enzyme shuttling fatty acids into mitochondria for β-oxidation
and energy production. Pharmacological inhibition of CPT1A combined with retinoic acid treatment resulted in
marked GBM cell death. Together, these novel preliminary data strongly support the hypothesis that 13-cis-RA
or ATRA can significantly alter lipid metabolism in GBM and promote fatty acid oxidation to support tumor cell
survival and resistance. We further hypothesize that retinoic acid treatment in combination with suppression of
SREBP-1 activation or fatty acid oxidation will effectively inhibit GBM growth and overcome tumor resistance.
The goal of this study is to identify the previously unreported roles and mechanisms of retinoic acids and RARα
in lipid metabolism regulation and GBM growth (Aim 1), and to develop effective combination approaches to
target GBM (Aim 2). Completion of this study will uncover the underlying mechanism upregulating SREBP-1
expression and lipogenesis in GBM, provide great insights into understanding the antitumor and resistance
mechanisms of retinoic acids, and identify novel strat...

## Key facts

- **NIH application ID:** 10168482
- **Project number:** 5R01CA240726-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Deliang Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $440,840
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168482

## Citation

> US National Institutes of Health, RePORTER application 10168482, Delineating how retinoic acids regulate lipid metabolism in glioblastoma and their resistance mechanisms (5R01CA240726-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10168482. Licensed CC0.

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