Data from The Neurofibromatosis Type 1 Tumor Suppressor Controls Cell Growth by Regulating Signal Transducer and Activator of Transcription-3 Activity <i>In vitro</i> and <i>In vivo</i>

Abstract

<div>Abstract<p>Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome in which affected individuals develop benign and malignant nerve tumors. The <i>NF1</i> gene product neurofibromin negatively regulates Ras and mammalian target of rapamycin (mTOR) signaling, prompting clinical trials to evaluate the ability of Ras and mTOR pathway inhibitors to arrest NF1-associated tumor growth. To discover other downstream targets of neurofibromin, we performed an unbiased cell-based high-throughput chemical library screen using <i>NF1</i>-deficient malignant peripheral nerve sheath tumor (MPNST) cells. We identified the natural product, cucurbitacin-I (JSI-124), which inhibited <i>NF1</i>-deficient cell growth by inducing apoptosis. We further showed that signal transducer and activator of transcription-3 (STAT3), the target of cucurbitacin-I inhibition, was hyperactivated in <i>NF1</i>-deficient primary astrocytes and neural stem cells, mouse glioma cells, and human MPNST cells through Ser<sup>727</sup> phosphorylation, leading to increased cyclin D1 expression. STAT3 was regulated in <i>NF1</i>-deficient cells of murine and human origin in a TORC1- and Rac1-dependent manner. Finally, cucurbitacin-I inhibited the growth of <i>NF1</i>-deficient MPNST cells <i>in vivo</i>. In summary, we used a chemical genetics approach to reveal STAT3 as a novel neurofibromin/mTOR pathway signaling molecule, define its action and regulation, and establish STAT3 as a tractable target for future NF1-associated cancer therapy studies. Cancer Res; 70(4); 1356–66</p></div>