AT101 Down‐regulates CXLC12 mRNA and Secreted Protein in Malignant Peripheral Nerve Sheath Tumor cells

Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Schwann cell‐derived neoplasms of the peripheral nervous system. MPNSTs have recently been shown to possess an autocrine CXCL12/CXCR4 signaling loop that promotes tumor cell proliferation and survival. Importantly, the CXCL12/CXCR4 axis is driven by availability of the CXCL12 ligand rather than CXCR4 receptor levels. Accordingly, pharmacological reduction of CXCL12 expression and/or secretion could be a potential chemotherapeutic option for patients with MPNSTs or other malignancies wherein the CXCL12/CXCR4 axis is relevant. AT101 is a polyphenolic cottonseed derivative with well‐established Bcl‐2 homology domain 3 (BH3)‐ mimetic properties. We recently reported that AT101 can also chelate intracellular iron and therefore act as a hypoxia mimetic. Importantly, we have observed that AT101 causes a marked reduction in CXCL12 mRNA and secreted protein levels in cultured MPNST cells. This property of AT101 was recapitulated by other BH3‐mimetics (ABT‐737, obatoclax and subatoclax) but not by desferrioxamine (DFO), an iron chelator and known hypoxia‐mimetic. These data indicate that CXCL12 reduction is likely a function of AT101′s BH3‐mimetic property rather than its iron chelation ability. Ongoing studies are aimed at addressing the mechanism by which AT101 and other BH3‐mimetics reduce CXCL12 mRNA and protein in MPNST cells.