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Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16375-80. doi: 10.1073/pnas.1113554108. Epub 2011 Sep 19.

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.

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1
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

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.

PMID:
21930909
PMCID:
PMC3182729
DOI:
10.1073/pnas.1113554108
[Indexed for MEDLINE]
Free PMC Article
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