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.
Keywords:
FOXM1; cancer signaling; differentiation; gastroenteropancreatic neuroendocrine neoplasms; siomycin A.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Aged, 80 and over
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Apoptosis / drug effects
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Cell Differentiation / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Forkhead Box Protein M1
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Forkhead Transcription Factors / antagonists & inhibitors*
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Intestinal Neoplasms / drug therapy*
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Intestinal Neoplasms / metabolism*
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Middle Aged
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Molecular Targeted Therapy
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Neuroendocrine Tumors / drug therapy*
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Neuroendocrine Tumors / metabolism*
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / metabolism*
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Peptides / pharmacology*
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / metabolism*
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Young Adult
Substances
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FOXM1 protein, human
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Forkhead Box Protein M1
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Forkhead Transcription Factors
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Peptides
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siomycin
Supplementary concepts
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Gastro-enteropancreatic neuroendocrine tumor