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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Genetic and small molecule inhibition of arylamine N-acetyltransferase 1 reduces anchorage-independent growth in human breast cancer cell line MDA-MB-231.

Authors: Stepp, Marcus W; Doll, Mark A; Carlisle, Samantha M; States, J Christopher; Hein, David W

Published In Mol Carcinog, (2018 Apr)

Abstract: Arylamine N-acetyltransferase 1 (NAT1) expression is reported to affect proliferation, invasiveness, and growth of cancer cells. MDA-MB-231 breast cancer cells were engineered such that NAT1 expression was elevated or suppressed, or treated with a small molecule inhibitor of NAT1. The MDA-MB-231 human breast cancer cell lines were engineered with a scrambled shRNA, a NAT1 specific shRNA or a NAT1 overexpression cassette stably integrated into a single flippase recognition target (FRT) site facilitating incorporation of these different genetic elements into the same genomic location. NAT1-specific shRNA reduced NAT1 activity in vitro by 39%, increased endogenous acetyl coenzyme A levels by 35%, and reduced anchorage-independent growth (sevenfold) without significant effects on cell morphology, growth rates, anchorage-dependent colony formation, or invasiveness compared to the scrambled shRNA cell line. Despite 12-fold overexpression of NAT1 activity in the NAT1 overexpression cassette transfected MDA-MB-231 cell line, doubling time, anchorage-dependent cell growth, anchorage-independent cell growth, and relative invasiveness were not changed significantly when compared to the scrambled shRNA cell line. A small molecule (5E)-[5-(4-hydroxy-3,5-diiodobenzylidene)-2-thioxo-1,3-thiazolidin-4-one (5-HDST) was 25-fold more selective towards the inhibition of recombinant human NAT1 than N-acetyltransferase 2. Incubation of MDA-MB-231 cell line with 5-HDST resulted in 60% reduction in NAT1 activity and significant decreases in cell growth, anchorage-dependent growth, and anchorage-independent growth. In summary, inhibition of NAT1 activity by either shRNA or 5-HDST reduced anchorage-independent growth in the MDA-MB-231 human breast cancer cell line. These findings suggest that human NAT1 could serve as a target for the prevention and/or treatment of breast cancer.

PubMed ID: 29315819 Exiting the NIEHS site

MeSH Terms: Arylamine N-Acetyltransferase/antagonists & inhibitors*; Arylamine N-Acetyltransferase/genetics*; Arylamine N-Acetyltransferase/metabolism; Binding Sites/genetics; Breast Neoplasms/enzymology; Breast Neoplasms/genetics; Breast Neoplasms/pathology; Cell Adhesion/drug effects; Cell Adhesion/genetics; Cell Line, Tumor; Cell Proliferation/drug effects*; Cell Proliferation/genetics; Female; Gene Expression Regulation, Enzymologic/drug effects; Gene Expression Regulation, Neoplastic/drug effects; Humans; Isoenzymes/antagonists & inhibitors*; Isoenzymes/genetics*; Isoenzymes/metabolism; Molecular Structure; RNA Interference; RNA, Small Interfering/genetics; Small Molecule Libraries/chemistry; Small Molecule Libraries/pharmacology*; Thiazolidines/chemistry; Thiazolidines/pharmacology*

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