TitleThe aryl hydrocarbon receptor is required for induction of p21cip1/waf1 expression and growth inhibition by SU5416 in hepatoma cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsO'Donnell, EF, Jang, HSang, Pearce, M, Kerkvliet, NI, Kolluri, S
JournalOncotarget
Volume8
Issue15
Pagination25211-25225
Date Published2017 Apr 11
ISSN1949-2553
KeywordsAntineoplastic Agents, Aryl Hydrocarbon Receptor Nuclear Translocator, Cell Line, Cell Proliferation, Cell Survival, Cyclin-Dependent Kinase Inhibitor p21, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Indoles, Liver Neoplasms, Protein Kinase Inhibitors, Pyrroles, Receptors, Aryl Hydrocarbon, Signal Transduction
Abstract

The aryl hydrocarbon receptor (AhR) is a potential clinical target for cancer and autoimmune dysfunction. Identifying selective AhR modulators that produce desirable clinical outcomes represents an opportunity for developing new anti-cancer agents. Repurposing clinically-used drugs with established safety profiles that activate the AhR represents a good starting place to pursue this goal. In this study, we characterized the AhR-dependent effects of SU5416 (Semaxanib) following its identification in a small-molecule library screen. SU5416 potently activated AhR-dependent reporter genes, induced AhR nuclear localization, facilitated AhR-DNA binding, and increased, expression of its endogenous target genes. SU5416 significantly inhibited proliferation of Hepa1 hepatoma cells in an AhR-dependent manner, but did not induce apoptosis. SU5416 also inhibited the growth of human HepG2 liver cancer cells. The effects of SU5416 correlated with an increased G1 population and increased expression of cell cycle inhibitor p21cip1/waf1 at both the mRNA and protein level. Increased expression of p21cip1/waf1 by SU5416 required expression of both AhR and Arnt. In addition, evidence for long-term activation of the AhR in vivo by a single dose of SU5416 was identified by analyzing published microarray data. Our results provide support for continued investigation of the AhR as therapeutic for cancers such as hepatocellular carcinoma. In addition, our findings raise the possibility that some of the previously observed anti-proliferative effects of SU5416 may be due to activation of the AhR.

DOI10.18632/oncotarget.16056
Alternate JournalOncotarget
PubMed ID28424418
PubMed Central IDPMC5421923
Grant ListP30 ES000210 / ES / NIEHS NIH HHS / United States
R01 ES016651 / ES / NIEHS NIH HHS / United States
R21 ES019000 / ES / NIEHS NIH HHS / United States
T32 ES007060 / ES / NIEHS NIH HHS / United States