# Project 2 - PCG-1 Signaling and Mitochondrial Stress in Melanoma

> **NIH NIH P01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $302,687

## Abstract

SUMMARY – PROJECT 2: PGC-1 SIGNALING AND MITOCHONDRIAL STRESS IN MELANOMA 
During the process of melanoma formation, progression, and treatment, dramatic changes in metabolism occur 
and are required for the evolving energetic and biosynthetic needs of rapidly proliferating cells. Mitochondria 
serve as a central integration point for this metabolic re-programming; regulating ATP synthetic capacity, redox 
signaling, and biosynthetic capability. Preliminary data presented in this P01 application demonstrate a 
dynamic feedback circuit in specific melanoma subsets involving ATF4, MITF, and PGC-1α transcription 
factors. The ATF4–MITF–PGC-1α axis is responsive to ER stress, nutrient deprivation, and melanoma driver 
mutations, and regulates responses to targeted therapies, ROS stress, and metabolic stress. This Project is 
focused on the role of the PGC-1 family of transcription coregulators, PGC-1α, PGC-1β, and PRC, in these 
processes. Recent evidence indicates that PGC-1α, a master regulator of mitochondrial biogenesis and 
function, is upregulated in a subset of melanomas together with MITF. Elevated PGC-1α expression correlates 
with increased mitochondrial content and oxygen consumption rates. Interestingly, inhibition of BRAF in this 
subset of melanomas results in further increase in mitochondrial content, oxygen consumption and induces 
sensitivity to mitochondrial respiratory inhibitors. The interplay between the ER stress/unfolded protein 
response and PGC-1α/mitochondria will be characterized in Project 1. Mitochondria and PGC-1α also integrate 
signals related to glutamine metabolism, a focus of Project 3. We hypothesize that mitochondrial functional 
capacity, as determined by the activity of PGC-1 factors, coordinates cellular stress responses and can 
be used to define susceptibility to mitochondrial-targeted agents for clinical intervention. To 
characterize the role of PGC-1α, PGC-1β, PRC and mitochondrial function in melanoma, we will (1) determine 
the functional role of the MITF/PGC-1α/ERRα pathway in the metabolic regulation of melanoma formation and 
treatment response and (2) evaluate the role of PGC-1β and PRC in melanoma metabolic regulation, stress 
responses, and sensitivity to therapeutic intervention. Our studies will be closely integrated with Projects 1 and 
3, and will require the use of Cores B and C.

## Key facts

- **NIH application ID:** 9925091
- **Project number:** 5P01CA128814-10
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** MARCUS W BOSENBERG
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $302,687
- **Award type:** 5
- **Project period:** — → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925091

## Citation

> US National Institutes of Health, RePORTER application 9925091, Project 2 - PCG-1 Signaling and Mitochondrial Stress in Melanoma (5P01CA128814-10). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9925091. Licensed CC0.

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