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

被引:25
|
作者
Taromi, Sanaz [1 ]
Lewens, Florentine [2 ]
Arsenic, Ruza [5 ]
Sedding, Dagmar [2 ]
Saenger, Jorg [4 ]
Kunze, Almut [4 ]
Moebs, Markus [5 ]
Benecke, Joana [2 ]
Freitag, Helma [2 ,11 ]
Christen, Friederike [2 ,6 ]
Kaemmerer, Daniel [7 ]
Lupp, Amelie [8 ]
Heilmann, Mareike [9 ]
Lammert, Hedwig [5 ]
Schneider, Claus-Peter [9 ]
Richter, Karen [9 ]
Hummel, Michael [5 ]
Siegmund, Britta [2 ]
Burger, Meike [1 ]
Briest, Franziska [2 ,3 ,10 ]
Grabowski, Patricia [2 ,10 ,11 ]
机构
[1] Univ Med Ctr, Dept Med, Div Hematol & Oncol, Freiburg, Germany
[2] Charite, Dept Gastroenterol, Infect Dis, Rheumatol CC13, Berlin, Germany
[3] FU, Dept Chem & Biochem, Berlin, Germany
[4] Inst Pathol, Bad Berka, Germany
[5] Charite, Inst Pathol, Berlin, Germany
[6] Humboldt Univ, Inst Biol, Berlin, Germany
[7] Zent Klin Bad Berka GmbH, Dept Gen & Visceral Surg, Bad Berka, Germany
[8] Jena Univ Hosp, Inst Pharmacol & Toxicol, Jena, Germany
[9] Zent Klin Bad Berka GmbH, Dept Oncol, Bad Berka, Germany
[10] Zent Klin Bad Berka GmbH, Dept Gastroenterol & Endocrinol, Bad Berka, Germany
[11] Charite, Dept Med Immunol, Berlin, Germany
关键词
FOXM1; in vivo; SCLC; mouse model; lung cancer; FORKHEAD BOX M1; SOUTHWEST-ONCOLOGY-GROUP; TRANSCRIPTION FACTOR; NEUROENDOCRINE TUMORS; MEDIATED APOPTOSIS; BREAST-CANCER; FOXM1; CONFERS; EXPRESSION; TARGET; PS-341;
D O I
10.18632/oncotarget.21221
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:97061 / 97078
页数:18
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