期刊
THERANOSTICS
卷 11, 期 15, 页码 7527-7545出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.54695
关键词
Arginine starvation; Epigenetic gene silencing; DNA leakage; cGAS-STING activation
资金
- Graduate Program of Biotechnology in Medicine, NTHU
- NHRI
- MOST [105-2314-B-400-019-MY3, 107-2320-B-038-055MY3, 105-2320-B-038-071-MY3, 108-2320-B-038-011-MY3]
- TMU Research Center of Cancer Translational Medicine
- Featured Areas Research Center Program/Higher Education Sprout Project
- Polaris Pharmaceuticals [ADI-PEG20]
The study revealed the mechanisms of tumor cell death induced by arginine starvation, including suppression of gene expression, changes in metabolic profiles, and activation of immune responses. The dietary arginine-restriction model demonstrated that arginine starvation can suppress prostate cancer growth and enhance immune cell recruitment.
Rationale: One of the most common metabolic defects in cancers is the deficiency in arginine synthesis, which has been exploited therapeutically. Yet, challenges remain, and the mechanisms of arginine-starvation induced killing are largely unclear. Here, we sought to demonstrate the underlying mechanisms by which arginine starvation-induced cell death and to develop a dietary arginine-restriction xenograft model to study the in vivo effects. Methods: Multiple castration-resistant prostate cancer cell lines were treated with arginine starvation followed by comprehensive analysis of microarray, RNA-seq and ChIP-seq were to identify the molecular and epigenetic pathways affected by arginine starvation. Metabolomics and Seahorse Flux analyses were used to determine the metabolic profiles. A dietary arginine-restriction xenograft mouse model was developed to assess the effects of arginine starvation on tumor growth and inflammatory responses. Results: We showed that arginine starvation coordinately and epigenetically suppressed gene expressions, including those involved in oxidative phosphorylation and DNA repair, resulting in DNA damage, chromatin-leakage and cGAS-STING activation, accompanied by the upregulation of type I interferon response. We further demonstrated that arginine starvation-caused depletion of alpha-ketoglutarate and inactivation of histone demethylases are the underlying causes of epigenetic silencing. Significantly, our dietary arginine-restriction model showed that arginine starvation suppressed prostate cancer growth in vivo, with evidence of enhanced interferon responses and recruitment of immune cells. Conclusions: Arginine-starvation induces tumor cell killing by metabolite depletion and epigenetic silencing of metabolic genes, leading to DNA damage and chromatin leakage. The resulting cGAS-STING activation may further enhance these killing effects.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据