The aryl hydrocarbon receptor is required for induction of p21cip1/waf1 expression and growth inhibition by SU5416 in hepatoma cells
Year: 2017
Type: article
Abstract: // Edmond F. O’Donnell 1, 2 , Hyo Sang Jang 1, 2 , Martin Pearce 1, 2 , Nancy I. Kerkvliet 2 , Siva Kumar Kolluri 1, 2 1 Cancer Research Laboratory, Oregon State University, Corvallis, Oregon, USA 2 Department of Environmental and Molecular Toxicology, and Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, USA Correspondence to: Siva Kumar Kolluri, email: [email protected] Keywords: AhR, proliferation, ligands, nuclear receptor, Arnt Received: September 12, 2016 Accepted: February 06, 2017 Published: March 09, 2017 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 p21 cip1/waf1 at both the mRNA and protein level. Increased expression of p21 cip1/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.
Source: Oncotarget
Institution: Oregon State University
Language: English
Subfield: Health, Toxicology and Mutagenesis
Field: Environmental Science
Domain: Physical Sciences
Open Access status: diamond
Awards: G1060374608, G1497661912, The AHR as a Novel Pathway to the Induction of Regulatory T cells, G4119534169, Reducing Susceptibility to Environmental Stress Throughout the Life Span, G470040766, G5915229349, Aryl Hydrocarbon Receptor Modulators for the Treatment of Hepatocellular Carcinom, Integrated Regional Training Program in Environmental Health Sciences (IRTP)
OpenAlex ID: W2591930043