# Metabolic Regulation of Tumor Progression, Metastasis and Chemoresistance by SIRT5/ELK3 signaling in Pancreatic Cancer

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2021 · $857

## Abstract

Pancreatic ductal adenocarcinomas (PDAC) are among the most lethal cancers because of
their extensive invasion into surrounding tissues and metastasis to distant organs, even during early stages of
tumor progression. The poor prognosis for this malignancy also reflects a generally poor response to current
therapies. Thus, understanding the biology of these tumors and the mechanisms that promote their invasion and
metastasis will provide a basis for developing new methods for diagnosis and treatment.
 Tumor cells display metabolic alterations that result in enhanced tumor growth or metastasis. Specifically,
metabolic reprogramming promotes tumor cell survival under harsh conditions during transit to distant sites and
induces proliferation once the tumor cells establish metastatic loci. Aberrant glutamine metabolism is associated
with tumor growth in Kras-driven pancreatic cancer. Likewise, our preliminary data demonstrate increased
dependence of metastatic lesions on glutamine metabolism. Additionally, we demonstrate that glutamine
metabolism regulates responsiveness against gemcitabine by regulating flux through the pyrimidine biosynthesis
pathway. We identify SIRT5 as a key negative regulator of glutamine metabolism that diminishes glutamine
uptake and dependence in pancreatic cancer cells. SIRT5 diminishes tumor growth and metastasis in orthotopic
models. We also observe that SIRT5 negatively regulates the expression of Elk-3, which promotes glutamine
metabolism, pancreatic cancer cell survival, and invasiveness. Of particular significance to the proposal, ELK3
is significantly overexpressed by advanced primary and metastatic pancreatic tumor lesions, and hence ELK3-
induced metabolic reprogramming is expected to be a target for suppressing pancreatic tumor progression and
metastasis.
 Our long-term goal is to determine the molecular basis of SIRT5/ELK3-mediated metabolic alterations
that facilitate progression and metastasis in pancreatic cancer. Here, we hypothesize that SIRT5/ELK3-
mediated regulation of glutamine metabolism contributes to tumor progression, metastasis, and
chemoresistance in PDAC. Furthermore, we hypothesize that targeting glutamine metabolism can provide
a therapeutic strategy to combat tumor progression, metastasis, and chemoresistance in PDAC. Here,
we propose to characterize the metabolic phenotype in SIRT5-deficient pancreatic tumor models (Aim 1) and
investigate if Elk3-mediated transcriptional and metabolic reprogramming contributes to SIRT5-mediated
metabolic phenotype (Aim 2). Furthermore, we propose to elucidate the role of ELK3 in regulating tumor
progression, metastasis, and gemcitabine resistance in PDAC (Aim 3). These studies will elucidate the metabolic
aspects of SIRT5/ELK3-mediated tumor progression and metastasis and are strongly expected to uncover
additional therapeutic strategies for the treatment of pancreatic cancer.

## Key facts

- **NIH application ID:** 10662933
- **Project number:** 7R01CA216853-06
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Pankaj Kumar Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $857
- **Award type:** 7
- **Project period:** 2017-03-20 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10662933

## Citation

> US National Institutes of Health, RePORTER application 10662933, Metabolic Regulation of Tumor Progression, Metastasis and Chemoresistance by SIRT5/ELK3 signaling in Pancreatic Cancer (7R01CA216853-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10662933. Licensed CC0.

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