Wild-type IDH1 maintains NSCLC stemness and chemoresistance through activation of the serine biosynthetic pathway

Author:

Zhang Cheng12ORCID,Yu Jiao-jiao1ORCID,Yang Chen1ORCID,Yuan Zhen-long3ORCID,Zeng Hui3ORCID,Wang Jun-jian4ORCID,Shang Shuang1ORCID,Lv Xiao-xi1ORCID,Liu Xiao-tong1ORCID,Liu Jing1ORCID,Xue Qi3,Cui Bing1,Tan Feng-wei3ORCID,Hua Fang1ORCID

Affiliation:

1. CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study (BZ0150), State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, P.R. China.

2. Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, P.R. China.

3. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P.R. China.

4. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, P.R. China.

Abstract

Tumor-initiating cells (TICs) reprogram their metabolic features to meet their bioenergetic, biosynthetic, and redox demands. Our previous study established a role for wild-type isocitrate dehydrogenase 1 (IDH1 WT ) as a potential diagnostic and prognostic biomarker for non–small cell lung cancer (NSCLC), but how IDH1 WT modulates NSCLC progression remains elusive. Here, we report that IDH1 WT activates serine biosynthesis by enhancing the expression of phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), the first and second enzymes of de novo serine synthetic pathway. Augmented serine synthesis leads to GSH/ROS imbalance and supports pyrimidine biosynthesis, maintaining tumor initiation capacity and enhancing gemcitabine chemoresistance. Mechanistically, we identify that IDH1 WT interacts with and stabilizes PHGDH and fragile X–related protein-1 (FXR1) by impeding their association with the E3 ubiquitin ligase parkin by coimmunoprecipitation assay and proximity ligation assay. Subsequently, stabilized FXR1 supports PSAT1 mRNA stability and translation, as determined by actinomycin D chase experiment and in vitro translation assay. Disrupting IDH1 WT -PHGDH and IDH1 WT -FXR1 interactions synergistically reduces NSCLC stemness and sensitizes NSCLC cells to gemcitabine and serine/glycine–depleted diet therapy in lung cancer xenograft models. Collectively, our findings offer insights into the role of IDH1 WT in serine metabolism, highlighting IDH1 WT as a potential therapeutic target for eradicating TICs and overcoming gemcitabine chemoresistance in NSCLC.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

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