title: Superoxide dismutase 1 (SOD1) is a target for a small molecule identified in a screen for inhibitors of the growth of lung adenocarcinoma cell lines.
abstract: We previously described four small molecules that reduced the growth of lung adenocarcinoma cell lines with either epidermal growth factor receptor (EGFR) or KRAS mutations in a high-throughout chemical screen. By combining affinity proteomics and gene expression analysis, we now propose superoxide dismutase 1 (SOD1) as the most likely target of one of these small molecules, referred to as lung cancer screen 1 (LCS-1). siRNAs against SOD1 slowed the growth of LCS-1 sensitive cell lines; conversely, expression of a SOD1 cDNA increased proliferation of H358 cells and reduced sensitivity of these cells to LCS-1. In addition, SOD1 enzymatic activity was inhibited in vitro by LCS-1 and two closely related analogs. These results suggest that SOD1 is an LCS-1-binding protein that may act in concert with mutant proteins, such as EGFR and KRAS, to promote cell growth, providing a therapeutic target for compounds like LCS-1.
authors.affiliation: High Throughput Screening Core Facility, and Organic Synthesis Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. somwarr@mskcc.org or harold.varmus@nih.gov
authors.forename: Romel
authors.initials: R
authors.lastname: Somwar
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
authors.forename: David
authors.initials: D
authors.lastname: Shum
authors.forename: William W
authors.initials: WW
authors.lastname: Lockwood
authors.forename: Guangli
authors.initials: G
authors.lastname: Yang
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tempst
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.forename: Harold E
authors.initials: HE
authors.lastname: Varmus
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D013482:Superoxide Dismutase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D034741:RNA, Small Interfering; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1