The neurofibromatosis type 1 tumor suppressor controls cell growth by regulating signal transducer and activator of transcription-3 activity in vitro and in vivo.

Cancer Research
Sutapa BanerjeeDavid H Gutmann

Abstract

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome in which affected individuals develop benign and malignant nerve tumors. The NF1 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 NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells. We identified the natural product, cucurbitacin-I (JSI-124), which inhibited NF1-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 NF1-deficient primary astrocytes and neural stem cells, mouse glioma cells, and human MPNST cells through Ser(727) phosphorylation, leading to increased cyclin D1 expression. STAT3 was regulated in NF1-deficient cells of murine and human origin in a TORC1- and Rac1-dependent manner. Finally, cucurbitacin-I inhibited the growth of NF1-deficient MPNST cells in vivo. In summary, we used...Continue Reading

Citations

Sep 8, 2011·Proceedings of the National Academy of Sciences of the United States of America·Sutapa BanerjeeDavid H Gutmann
Apr 23, 2011·Medicine·David MontaniFlorent Soubrier
Apr 18, 2012·Genes & Development·Gavin P DunnWilliam C Hahn
May 7, 2015·Acta Neuropathologica·Kenneth AldapeAndreas von Deimling
Jan 5, 2012·Cell Cycle·Jason D Weber, David H Gutmann
Jun 9, 2016·Seminars in Cell & Developmental Biology·Laura J SmithsonDavid H Gutmann
Nov 9, 2016·Scientific Reports·Shizhi WangMeilin Wang
Jan 31, 2017·Annual Review of Pathology·Courtney L MonroeDavid H Gutmann
May 23, 2015·PLoS Computational Biology·Matthew H UngChao Cheng
Mar 7, 2014·The Journal of Biological Chemistry·Guang YuanGang Li
Aug 31, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Zhimin HuYu Li
Aug 10, 2013·Otology & Neurotology : Official Publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology·Samuel A SpearLong-Sheng Chang
Mar 17, 2016·Oncotarget·Yi-Hsien ChenDavid H Gutmann
May 23, 2020·British Journal of Cancer·Jean-Philippe BrosseauLu Q Le
Jul 16, 2014·Oncotarget·Yoon-Sim YapDavid F Callen
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Oct 17, 2020·Cancer Cell International·Junyan TaoHelei Hou
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