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// 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: siva.kolluri@oregonstate.edu 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.

// Martin C. Pearce 1 , John T. Gamble 1, 2 , Prasad R. Kopparapu 1 , Edmond F. O'Donnell 1 , Monica J. Mueller 1 , Hyo Sang Jang 1 , Julie A. Greenwood 2 , Arnold C. Satterthwait 3 , Robert L. Tanguay 4, 5, 6 , Xiao-Kun Zhang 3 and Siva Kumar Kolluri 1, 4, 5, 6 1 Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA 2 Department of Biochemistry & Biophysics, Oregon State University, Corvallis, Oregon 97331, USA 3 Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92031, USA 4 Department of Environmental & Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon 97331, USA 5 Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA 6 Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR 97331, USA Correspondence to: Siva Kumar Kolluri, email: siva.kolluri@oregonstate.edu Keywords: chemoresistance; Bcl-2; NuBCP-9; paclitaxel; lung cancer Received: February 19, 2018 Accepted: April 24, 2018 Published: May 25, 2018 ABSTRACT Resistance to chemotherapy is a major cause of treatment failure and poor overall survival in patients with lung cancer. Identification of molecular targets present in resistant cancer cells is essential for addressing therapeutic resistance and prolonging lung cancer patient survival. Members of the B-cell lymphoma 2 (Bcl-2) family of proteins are associated with chemotherapeutic resistance. In this study, we found that pro-survival protein Bcl-2 is upregulated in paclitaxel resistant cells, potentially contributing to chemotherapy resistance. To exploit the increase in Bcl-2 expression for targeting therapy resistance, we investigated the effects of a peptide derived from the nuclear receptor Nur77 that converts Bcl-2 from an anti-apoptotic protein to a pro-apoptotic protein. The Nur77 derived peptide preferentially induced apoptosis in paclitaxel-resistant cancer cells with high expression of Bcl-2. This peptide also induced apoptosis of multidrug resistant H69AR lung cancer cells that express Bcl-2 and inhibited their growth in 3D spheroids. The Nur77 peptide strongly suppressed the growth of paclitaxel-resistant lung cancer cells in a zebrafish xenograft tumor model. Taken together, our data supports a new strategy for treating lung cancers that acquire resistance to chemotherapy through overexpression of Bcl-2.