Targeting TRAF3IP2 disrupts cellular energetics through inhibition of NAMPT in triple negative breast cancer

TL;DR

Disrupting TRAF3IP2 in triple-negative breast cancer cells reduces energy production and increases cell death by affecting key metabolic pathways.

Contribution

This study reveals that TRAF3IP2 inhibition disrupts cellular energetics in TNBC by targeting NAMPT and altering metabolic pathways.

Findings

TRAF3IP2 inhibition decreases NAMPT expression and NAD/ATP production in TNBC cells.

Disruption of TRAF3IP2 affects AMPK/LKB1 and mTOR pathways, increases ROS, and reduces cell viability.

Metabolic heterogeneity is observed between TNBC models like MDA-MB-231 and 4IC based on OCR responses.

Abstract

Triple-negative breast cancer (TNBC) is characterized by extensive metabolic alterations that enable its sustained growth therapeutic resistance. Nicotinamide phosphoribyltransferase (NAMPT) catalyzes the first and rate-limiting step in the nicotinamide dinucleotide (NAD) salvage pathway. Elevated NAMPT is associated with increased aggressiveness and poor prognosis in multiple cancers. Previously, we showed the role of TRAF3IP2 in TNBC tumorigenesis. Here, we aim to show that the anti-tumorigenic effects resulting from TRAF3IP2 inhibition are driven in part by decreases in cellular energetics in TNBC cells. Results show that inhibition of TRAF3IP2 leads to significant decrease in NAMPT expression, reduced NAD and ATP production, and disruption of TNBC bioenergetics through cell line-specific alterations in glycolysis and mitochondrial function. Notably, the established MDA-MB-231 line and the patient-derived 4IC model exhibited distinct OCR responses, underscoring metabolic heterogeneity across TNBC models. Additionally, this study showed that targeting TRAF3IP2 disrupts cellular energetics by affecting AMPK/LKB1 and mTOR signaling pathways and increasing reactive oxygen species (ROS) levels, ultimately leading to reduced cell viability and increased apoptosis. These findings suggest that TRAF3IP2 plays a critical role in maintaining TNBC bioenergetics and represents a potential target for therapeutic intervention.

The online version contains supplementary material available at 10.1038/s41598-025-29057-4.

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