Biology subjects

Kung, C.-P.

Publications and source records attributed to Kung, C.-P..

3 recordsLinked to original sources

bioRxiv2025

ADAR1 Regulates Lipid Remodeling through MDM2 to Dictate Ferroptosis Sensitivity

Triple-negative breast cancer (TNBC), defined by the lack of estrogen, progesterone, and HER2 receptor expressions, is aggressive and lacks targeted treatment options. Adenosine deaminase acting on RNA 1 (ADAR1) has been shown to contribute to TNBC tumorigenesis by modulating an innate immune response. However, little is known about its role in the regulation of metabolic fitness of TNBC. We tested the hypothesis that ferroptosis is an ADAR1-protected vulnerability by showing that ADAR1 knockdown sensitizes TNBC cells to ferroptosis inducers. Lipidomic analyses showed that ADAR1 loss increased the abundance of phospholipids enriched with polyunsaturated fatty acids (PUFA), of which peroxidation is the main driver of ferroptosis. Transcriptomic analyses discovered that the proto-oncogene MDM2 contributes to the lipid remodeling phenotype. A ferroptosis-focused drug screen identified FDA-approved cobimetinib as a drug-repurposing candidate to synergize with ADAR1 loss. This finding supports further basic, pre-clinical, and clinical studies to develop novel therapeutic strategies for TNBC through ADAR1-mediated metabolic regulation.

cancer biology↗

bioRxiv2020

Increased mTOR activity and metabolic efficiency in mouse and human cells containing the African-centric tumor-predisposing p53 variant Pro47Ser

The Pro47Ser variant of p53 exists in African-descent populations, and is associated with increased cancer risk in humans and mice. This variant, hereafter S47, shows altered regulation of the cystine importer Slc7a11, and S47 cells possess increased cysteine and glutathione (GSH) accumulation compared to cells with wild type p53. In this study we show that mice containing the S47 variant have increased mTOR activity, increased oxidative metabolism, larger size, and improved metabolic efficiency. Mechanistically, we show that there is increased association between mTOR and its positive regulator Rheb in S47 cells, due to altered redox state of GAPDH, which normally binds and sequesters Rheb. Compounds that decrease glutathione in S47 cells normalize GAPDH-Rheb complex formation and mTOR activity. The enhanced metabolic efficiency may have been selected for in early Africa, making the S47 variant one of a growing number of cancer-predisposing genetic variants that possesses other positive, potentially selectable attributes.

cancer biology↗

bioRxiv2020

ADAR1 editing dependency in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the deadliest form of breast cancer. Unlike other types of breast cancer that can be effectively treated by targeted therapies, no such targeted therapy exists for all TNBC patients. The ADAR1 enzyme carries out A-to-I editing of RNA to prevent sensing of cellular double-stranded RNAs (dsRNA). ADAR1 is highly expressed in breast cancer including TNBC. Here, we demonstrate that ADAR1 expression and editing activity is required in TNBC cell lines but not in ER+ and/or Her2+ cells. In TNBC cells, knockdown of ADAR1 attenuates proliferation and tumorigenesis. PKR expression is elevated in TNBC and its activity is induced upon ADAR1-knockdown, which correlates with a decrease in translation. ADAR1-dependent TNBC cell lines also exhibit elevated IFN stimulated gene expression. IFNAR1 reduction significantly rescues the proliferative defects of ADAR1 loss. These findings establish ADAR1 as a novel therapeutic target for TNBC tumors.

cancer biology↗