Oncotarget

Research Papers:

Proteasome inhibitor bortezomib enhances the effect of standard chemotherapy in small cell lung cancer

Sanaz Taromi, Florentine Lewens, Ruza Arsenic, Dagmar Sedding, Jörg Sänger, Almut Kunze, Markus Möbs, Joana Benecke, Helma Freitag, Friederike Christen, Daniel Kaemmerer, Amelie Lupp, Mareike Heilmann, Hedwig Lammert, Claus-Peter Schneider, Karen Richter, Michael Hummel, Britta Siegmund, Meike Burger, Franziska Briest _ and Patricia Grabowski

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Oncotarget. 2017; 8:97061-97078. https://doi.org/10.18632/oncotarget.21221

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Abstract

Sanaz Taromi1, Florentine Lewens2, Ruza Arsenic5, Dagmar Sedding2, Jörg Sänger4, Almut Kunze4, Markus Möbs5, Joana Benecke2, Helma Freitag2,11, Friederike Christen2,6, Daniel Kaemmerer7, Amelie Lupp8, Mareike Heilmann9, Hedwig Lammert5, Claus-Peter Schneider9, Karen Richter9, Michael Hummel5, Britta Siegmund2, Meike Burger1, Franziska Briest2,3,10,* and Patricia Grabowski2,10,11*

1Department of Medicine, Division of Hematology and Oncology, University Medical Center, Freiburg, Germany

2Department of Gastroenterology, Infectious Diseases, Rheumatology CC13, Charité-Universitätsmedizin, Berlin, Germany

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

4Institute of Pathology, Bad Berka, Germany

5Institute of Pathology, Charité-Universitätsmedizin, Berlin, Germany

6Institute of Biology, Humboldt-Universität, Berlin, Germany

7Department of General and Visceral Surgery, Zentralklinik Bad Berka GmbH, Bad Berka, Germany

8Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany

9Department for Oncology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany

10Department of Gastroenterology and Endocrinology, Zentralklinik Bad Berka GmbH, Bad Berka, Germany

11Department of Medical Immunology, Charité Universitätsmedizin, Berlin, Germany

*These authors have contributed equally to this work

Correspondence to:

Franziska Briest, email: franziska.briest@charite.de

Keywords: FOXM1, in vivo, SCLC, mouse model, lung cancer

Received: January 26, 2016     Accepted: August 04, 2017    Published: September 23, 2017

ABSTRACT

Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A. FOXM1 was strongly expressed in patient-derived SCLC samples (n=123) and its nuclear localization was associated with the proliferation marker Ki-67. Both proteasome inhibitors successfully inhibited FOXM1 expression leading to a significantly reduced proliferation and a decreased mitotic rate along with cell cycle arrest and apoptosis induction. These effects were further enhanced by addition of bortezomib to standard chemotherapy. Treatment of mice bearing chemoresistant SCLC xenografts with bortezomib reduced the mean bioluminescence signal of tumors by 54%. Similarly, treatment with cisplatin as a standard chemotherapy reduced the mean bioluminescence signal of tumors by 58%. However, in combination with standard chemotherapy bortezomib further reduced the mean bioluminescence signal by 93% (p=0.0258). In conclusion, we demonstrate the effect of bortezomib in inhibiting FOXM1 expression and thus in sensitizing resistant SCLC cells to standard chemotherapy. Thus, addition of bortezomib to standard chemotherapy might potently improve SCLC therapy, particularly in an extensive cancer stage.


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