# Investigating the Role of Reduced Branched-Chain Amino Acid Catabolism in Clear Cell Renal Cell Carcinoma

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2022 · $51,752

## Abstract

PROJECT SUMMARY
 North America has the highest incidence of renal cancer in the world with the most common subtype
being clear cell renal cell carcinoma (ccRCC). Alarmingly, the incidence of ccRCC is on the rise in the U.S. and
globally. The overall five-year survival rate for ccRCC is only 10-12% once it becomes metastatic,
demonstrating the need for new therapies. Metabolic dysfunction is common in ccRCC based on histologic and
molecular analysis. New therapies to treat ccRCC could target its dysregulated metabolic pathways. The
etiology of ccRCC is complex but a major risk factor is obesity. High levels of branched-chain amino acids
(BCAAs) are present in the serum of patients with ccRCC and obesity, suggesting a potential mechanistic link.
BCAAs (leucine, isoleucine, and valine) are essential amino acids, whose concentrations are regulated by
dietary intake and catabolism. BCAA metabolism promotes tumor growth in many different types of cancer, but
the role of BCAAs in ccRCC is unknown. BCAA catabolism occurs primarily via the first two enzymes, BCAA
transaminase (BCAT) and branched chain ketoacid dehydrogenase (BCKDH), respectively. BCKDH is an
enzyme complex that catalyzes the rate-limiting reaction. The products of BCAA catabolism are then oxidized
within the mitochondria to produce succinyl-CoA and acetyl-CoA, which can be used by the TCA cycle for
anaplerosis and mitochondrial respiration.
 My preliminary data demonstrate that BCAA catabolic enzyme BCAT2 and BCKDH subunits are
frequently reduced in human ccRCC tumors compared to normal adjacent kidney tissue (NAT). This decreased
expression occurs as early as stage 1 and is associated with reduced overall survival. Additionally, BCAAs and
their catabolic metabolites are decreased in ccRCC. These results suggest that BCAA catabolism is reduced
early in ccRCC and contributes to ccRCC aggressiveness. ccRCC may reduce BCAA metabolism to decrease
mitochondrial respiration and ROS because ccRCC is susceptible to ROS due to the large amount of
intracellular lipids that can undergo peroxidation. ccRCC decreases mitochondrial respiration and ROS by
downregulating genes involved in fatty acid oxidation and oxidative phosphorylation. I hypothesize that
reduced BCAA metabolism promotes ccRCC cell growth and tumorigenesis, and does so by
decreasing mitochondrial respiration and the production of ROS. Aim 1 will determine how reduced
BCAA catabolism promotes ccRCC cell growth in vitro. I will use genetic and pharmacologic approaches to
assess how gain or loss of BCAA metabolism affects proliferation of ccRCC and immortalized renal epithelial
cell lines. Aim 2 will identify how reduced BCAA catabolism contributes to ccRCC tumorigenesis in vivo. I will
use novel genetic mouse models to determine the role of BCAA catabolic flux on renal epithelial cell function
and ccRCC tumorigenesis. Together, these approaches will identify the mechanisms by which BCAA
catabolism regulates ccRCC tumorigenesis and ident...

## Key facts

- **NIH application ID:** 10464235
- **Project number:** 1F30CA271654-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Nathan Jackson Coffey
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464235

## Citation

> US National Institutes of Health, RePORTER application 10464235, Investigating the Role of Reduced Branched-Chain Amino Acid Catabolism in Clear Cell Renal Cell Carcinoma (1F30CA271654-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10464235. Licensed CC0.

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