Targeting De Novo NAD+ Synthesis Through the Kynurenine Pathway in Renal Cell Carcinoma
Abstract
Cancer cells alter their metabolism to meet the energetic and biosynthetic demands of malignant tumors and evade immune surveillance. Renal cell carcinomas (RCC) undergo substantial metabolic remodeling are considered a metabolic disease by some researchers. The kynurenine pathway converts tryptophan to nicotinamide adenine dinucleotide (NAD+) and is commonly activated in RCC. Kynurenine metabolism shows promise as both a mechanistic driver of pathology and a therapeutic target. Kynurenine metabolism provides two advantages to tumor cells: tryptophan depletion in the local microenvironment suppresses T cells while NAD+ production supports high energy and redox demands. Tryptophan-mediated immune evasion is widely studied while the role of de novo NAD+ synthesis has been relatively neglected. We hypothesized that preventing NAD+ synthesis via kynurenine metabolism would inhibit RCC and progression. We tested this hypothesis by knocking down three kynurenine pathway enzymes - HAAO, KMO, and QPRT - in RCC cell lines and measured malignant phenotypes both in vitro (Aim 1) and in vivo (Aim 2). RCC cell lines lacking HAAO, but not KMO or QPRT, exhibited several metrics of increased proliferation in culture. Surprisingly, RCC cell lines lacking all three enzymes produced tumors that were less lethal in vivo, suggesting that these modifications produce less aggressive tumors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2023
- Accession Number
- AD1229686
Entities
People
- George L Sutphin
Organizations
- University of Arizona