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.
Highlights
Lung cancer is still the leading cause of cancerrelated death worldwide [1]
High immunoreactivity for nuclear Forkhead box protein M1 (FOXM1) was detected in 47.3% (58/123) of the Small cell lung cancer (SCLC) samples, whereas only 29.4% (5/17) of the atypical carcinoid (ATC) samples and 9.1% (1/11) of the typical carcinoid (TC) samples were positively stained for nuclear FOXM1
Nuclear FOXM1 expression was related to the aggressiveness of the neuroendocrine lung cancer entity (p=0.026)
Summary
Small cell lung cancer (SCLC) accounts for 15-20% of all lung cancer cases and is characterized by an aggressive disease progression [2, 3]. It is often diagnosed at a late stage with frequent metastases [4]. SCLC reacts highly sensitive to chemo- and radiotherapy at the initial treatment step, most patients develop a tumor relapse, resulting in a poor median survival period of 9-12 months [5, 6]. The high mortality rate of those patients is due to acquired chemotherapy resistance [7]. Novel therapeutics strategies targeting resistance mechanisms are urgently needed
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