Oncotarget

Research Papers:

Characterization of CADD522, a small molecule that inhibits RUNX2-DNA binding and exhibits antitumor activity

Myoung Sook Kim _, Ramkishore Gernapudi, Eun Yong Choi, Rena G. Lapidus and Antonino Passaniti

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Oncotarget. 2017; 8:70916-70940. https://doi.org/10.18632/oncotarget.20200

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Abstract

Myoung Sook Kim1,3,4, Ramkishore Gernapudi2,3, Eun Yong Choi3, Rena G. Lapidus3 and Antonino Passaniti1,2,3,4

1Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA

2Department of Biochemistry & Molecular Biology and Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

3The Marlene & Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

4The Veteran’s Health Administration Research & Development Service, Baltimore, MD, USA

Correspondence to:

Myoung Sook Kim, email: [email protected]

Antonino Passaniti, email: [email protected]

Keywords: breast cancer, RUNX2, therapeutics

Received: March 24, 2017    Accepted: July 12, 2017    Published: August 10, 2017

ABSTRACT

The RUNX2 transcription factor promotes breast cancer growth and metastasis through interactions with a variety of cofactors that activate or repress target genes. Using a direct drug discovery approach we identified CADD522 as a small molecule that inhibits the DNA binding of the runt box domain protein, RUNX2. The current study defines the effect of CADD522 on breast cancer growth and metastasis, and addresses the mechanisms by which it exerts its anti-tumor activity.

CADD522 treatment resulted in significant growth inhibition, clonogenic survival, tumorsphere formation, and invasion of breast cancer cells. CADD522 negatively regulated transcription of RUNX2 target genes such as matrix metalloproteinase-13, vascular endothelial growth factor and glucose transporter-1, but upregulated RUNX2 expression by increasing RUNX2 stability. CADD522 reduced RUNX2-mediated increases in glucose uptake and decreased the level of CBF-β and RUNX2 phosphorylation at the S451 residue. These results suggest several potential mechanisms by which CADD522 exerts an inhibitory function on RUNX2-DNA binding; interference with RUNX2 for the DNA binding pocket, inhibition of glucose uptake leading to cell cycle arrest, down-regulation of CBF-β, and reduction of S451-RUNX2 phosphorylation.

The administration of CADD522 into MMTV-PyMT mice resulted in significant delay in tumor incidence and reduction in tumor burden. A significant decrease of tumor volume was also observed in a CADD522-treated human triple-negative breast cancer-patient derived xenograft model. CADD522 impaired the lung retention and outgrowth of breast cancer cells in vivo with no apparent toxicity to the mice. Therefore, by inhibiting RUNX2-DNA binding, CADD522 may represent a potential antitumor drug.


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