posted on 2023-04-03, 20:00authored byShideh Mirhadi, Wen Zhang, Nhu-An Pham, Fereshteh Karimzadeh, Melania Pintilie, Jiefei Tong, Paul Taylor, Jonathan Krieger, Bethany Pitcher, Jenna Sykes, Leanne Wybenga-Groot, Christopher Fladd, Jing Xu, Tao Wang, Michael Cabanero, Ming Li, Jessica Weiss, Shingo Sakashita, Olga Zaslaver, Man Yu, Amy A. Caudy, Julie St-Pierre, Cynthia Hawkins, Thomas Kislinger, Geoffrey Liu, Frances A. Shepherd, Ming-Sound Tsao, Michael F. Moran
Statistical association of clinical and pathologic characteristics with engraftment
Funding
Canadian Cancer Society (CCS)
Canadian Institutes of Health Research (IRSC)
Canada Foundation for Innovation (CFI)
Canada Research Chairs (Chaires de recherche du Canada)
Natural Sciences and Engineering Research Council of Canada (NSERC)
Genome Canada (GC)
History
ARTICLE ABSTRACT
The ability of a patient tumor to engraft an immunodeficient mouse is the strongest known independent indicator of poor prognosis in early-stage non–small cell lung cancer (NSCLC). Analysis of primary NSCLC proteomes revealed low-level expression of mitochondrial aconitase (ACO2) in the more aggressive, engrafting tumors. Knockdown of ACO2 protein expression transformed immortalized lung epithelial cells, whereas upregulation of ACO2 in transformed NSCLC cells inhibited cell proliferation in vitro and tumor growth in vivo. High level ACO2 increased iron response element binding protein 1 (IRP1) and the intracellular labile iron pool. Impaired cellular proliferation associated with high level ACO2 was reversed by treatment of cells with an iron chelator, whereas increased cell proliferation associated with low level ACO2 was suppressed by treatment of cells with iron. Expression of CDGSH iron-sulfur (FeS) domain-containing protein 1 [CISD1; also known as mitoNEET (mNT)] was modulated by ACO2 expression level and inhibition of mNT by RNA interference or by treatment of cells with pioglitazone also increased iron and cell death. Hence, ACO2 is identified as a regulator of iron homeostasis and mNT is implicated as a target in aggressive NSCLC.
FeS cluster–associated proteins including ACO2, mNT (encoded by CISD1), and IRP1 (encoded by ACO1) are part of an “ACO2–Iron Axis” that regulates iron homeostasis and is a determinant of a particularly aggressive subset of NSCLC.