title: EGFR regulates iron homeostasis to promote cancer growth through redistribution of transferrin receptor 1.
abstract: Dysregulation in iron metabolism can lead to a wide range of diseases including cancer. Iron-regulatory proteins (IRPs) and iron responsive elements (IREs) have been established as post-transcriptional regulators of intracellular iron homeostasis. The roles of other pathways involved in this process, however, remain largely unknown. Here we report that epidermal growth factor receptor (EGFR), an oncogenic driver, binds to and regulates the subcellular distribution of transferrin receptor 1(TfR1) through its tyrosine kinase activity and thus is required for cellular iron import. Inactivation of EGFR reduces the cell surface TfR1 expression, which leads to decreased iron import due to impaired TfR1-mediated iron uptake. This damaged iron assimilation results in cell cycle arrest and growth inhibition, which can be partially rescued by non-Tf-bound iron supplements. Evaluation of non-small cell lung cancer samples reveals a positive correlation between EGFR activation and membrane TfR1 expression. Our findings uncover a new role of EGFR in modulating cellular iron homeostasis through redistribution of TfR1, which is essential for cancer development and progression.
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Biao
authors: B
authors: Wang
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Jiqin
authors: J
authors: Zhang
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Fei
authors: F
authors: Song
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Mi
authors: M
authors: Tian
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Bizhi
authors: B
authors: Shi
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Hua
authors: H
authors: Jiang
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Wen
authors: W
authors: Xu
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Hai
authors: H
authors: Wang
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Min
authors: M
authors: Zhou
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Xiaorong
authors: X
authors: Pan
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Jianren
authors: J
authors: Gu
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
authors: Shengli
authors: S
authors: Yang
authors: Respiratory Department, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, No. 214, West Huaihai Road, Shanghai 200030, China. Electronic address: jiang_liyan2000@126.com.
authors: Liyan
authors: L
authors: Jiang
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China. Electronic address: zonghaili@shsmu.edu.cn.
authors: Zonghai
authors: Z
authors: Li
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000201:enzymology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D047428:Protein Kinase Inhibitors; D011990:Receptors, Transferrin; D007501:Iron; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; Iron homeostasis; TfR1; Tyrosine phosphorylation