BH3 mimetics suppress CXCL12 expression in human malignant peripheral nerve sheath tumor cells

// Christopher D. Graham 1 , Niroop Kaza 1 , Hawley C. Pruitt 1 , Lauren M. Gibson 1 , Barbara J. Klocke 1 , Lalita A. Shevde 1 , Steven L. Carroll 1, 2 , Kevin A. Roth 1, 3 1 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America 2 Current Address: Medical University of South Carolina, Department of Pathology and Laboratory Medicine, Charleston, South Carolina, United States of America 3 Current Address: Columbia University Medical Center, Department of Pathology and Cell Biology, New York, United States of America Correspondence to: Kevin A. Roth, email: kar2208@cumc.columbia.edu Keywords: MPNST, BH3 mimetic, CXCL12, PARP1, AT101 Received: July 13, 2016     Accepted: December 05, 2016     Published: December 31, 2016 ABSTRACT Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Schwann cell-derived neoplasms of the peripheral nervous system that have recently been shown to possess an autocrine CXCL12/CXCR4 signaling loop that promotes tumor cell proliferation and survival. Importantly, the CXCL12/CXCR4 signaling axis is driven by availability of the CXCL12 ligand rather than CXCR4 receptor levels alone. Therefore, pharmacological reduction of CXCL12 expression could be a potential chemotherapeutic target for patients with MPNSTs or other pathologies wherein the CXCL12/CXCR4 signaling axis is active. AT101 is a well-established BCL-2 homology domain 3 (BH3) mimetic that we recently demonstrated functions as an iron chelator and thus acts as a hypoxia mimetic. In this study, we found that AT101 significantly reduces CXCL12 mRNA and secreted protein in established human MPNST cell lines in vitro . This effect was recapitulated by other BH3 mimetics [ABT-737 (ABT), obatoclax (OBX) and sabutoclax (SBX)] but not by desferrioxamine (DFO), an iron chelator and known hypoxia mimetic. These data suggest that CXCL12 reduction is a function of AT101’s BH3 mimetic property rather than its iron chelation ability. Additionally, this study investigates a potential mechanism of BH3 mimetic-mediated CXCL12 suppression: liberation of a negative CXCL12 transcriptional regulator, poly (ADP-Ribose) polymerase I (PARP1) from its physical interaction with BCL-2. These data suggest that clinically available BH3 mimetics might prove therapeutically useful at least in part by virtue of their ability to suppress CXCL12 expression.