Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in Hurthle cell carcinoma of the thyroid.
Anderson R FrankVicky LiSpencer D SheltonJiwoong KimGordon M StottLeonard M NeckersYang XieNoelle S WilliamsPrashant MishraDavid G McFaddenPublished in: Cancer discovery (2023)
A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hurthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR-Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant HTC cells. We demonstrate in cultured cells and a PDX model that small molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.
Keyphrases
- oxidative stress
- induced apoptosis
- mitochondrial dna
- cell cycle arrest
- cell death
- small molecule
- crispr cas
- papillary thyroid
- copy number
- squamous cell
- genome editing
- public health
- endoplasmic reticulum stress
- gene expression
- dna methylation
- saccharomyces cerevisiae
- pi k akt
- randomized controlled trial
- adipose tissue
- lymph node metastasis
- young adults
- skeletal muscle
- metabolic syndrome
- protein protein
- wild type