Oncotarget

Research Papers:

FOXM1: A novel drug target in gastroenteropancreatic neuroendocrine tumors

Franziska Briest, Erika Berg, Irina Grass, Helma Freitag, Daniel Kaemmerer, Florentine Lewens, Friederike Christen, Ruza Arsenic, Annelore Altendorf-Hofmann, Almut Kunze, Jörg Sänger, Thomas Knösel, Britta Siegmund, Michael Hummel and Patricia Grabowski _

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Oncotarget. 2015; 6:8185-8199. https://doi.org/10.18632/oncotarget.3600

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Abstract

Franziska Briest1,3, Erika Berg2, Irina Grass1,3, Helma Freitag1, Daniel Kaemmerer5, Florentine Lewens1, Friederike Christen1,10, Ruza Arsenic9, Annelore Altendorf-Hofmann8, Almut Kunze7, Jörg Sänger7, Thomas Knösel4, Britta Siegmund1, Michael Hummel2 and Patricia Grabowski1,6

1 Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Medizinische Klinik 1, CBF, Germany

2 Institute of Pathology, CBF, Charité - Universitätsmedizin Berlin, Germany

3 Department of Chemistry and Biochemistry, Freie Universität (FU) Berlin, Germany

4 Institute of Pathology, Ludwig-Maximilians-Universität (LMU), Munich, Germany

5 Department of General and Visceral Surgery, Zentralklinik Bad Berka GmbH, Germany

6 Department of Internal Oncology and Hematology, Zentralklinik Bad Berka GmbH, Germany

7 Institute of Pathology, Bad Berka, Germany

8 Department of General, Visceral and Vascular Surgery, Friedrich-Schiller-Universität (FSU) Jena, Germany

9 Institute of Pathology, CCM, Charité-Universitätsmedizin Berlin, Germany

10 Institute of Biology, Humboldt-Universität Berlin, Germany

Correspondence to:

Patricia Grabowski, email:

Keywords: gastroenteropancreatic neuroendocrine neoplasms, FOXM1, siomycin A, differentiation, cancer signaling

Received: September 24, 2014 Accepted: January 20, 2015 Published: March 15, 2015

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors that need to be molecularly defined to obtain novel therapeutic options. Forkheadbox protein M1 (FOXM1) is a crucial transcription factor in neoplastic cells and has been associated with differentiation and proliferation. We found that FOXM1 is strongly associated with tumor differentiation and occurrence of metastases in gastrointestinal NENs. In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect. Siomycin A decreased mitosis rate, induced apoptosis in GEP-NEN cell lines and exerts synergistic effects with chemotherapy. FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro. We therefore propose FOXM1 as novel therapeutic target in GEP-NENs.


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