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FOXM1: A novel drug target in gastroenteropancreatic neuroendocrine tumors.

Briest F, Berg E, Grass I, Freitag H, Kaemmerer D, Lewens F, Christen F, Arsenic R, Altendorf-Hofmann A, Kunze A, Sänger J, Knösel T, Siegmund B, Hummel M, Grabowski P - Oncotarget (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus

Cell cycle analysis of GEP-NEN cell lines treated with siomycin AUnsynchronized BON, QGP-1, KRJ-1, LCC-18 cells were treated with 2μM siomycin A for 96h and analyzed by mitotic index flow cytometry. Cells were stained with an anti-phospho-H3 antibody and propidium iodide and analyzed versus 0.04% DMSO controls. All changes were calculated with respect to DMSO controls. A. Average of cell cycle changes in the distinct GEP-NEN cell lines after Siomycin A treatment. BON cells show a strong 72-fold increase in the sub-G1 cell death population; in KRJ-1, QGP-1 and LCC-18 cells a 5- to 9-fold increase could be detected. Most notably, the number of mitotic cells (indicated by phosphorylated histone H3) significantly decreases after siomycin A treatment in the range of 6.5- to 16-fold. B. Representative histogram of one 96h incubation experiment, blue line indicates the DMSO control, red lines visualizes the cell cycle histogram after siomycin A treatment (more detailed flow cytometry data can be found in Suppl. 2). The average chances of all cell lines under siomycin A treatment are visualized in C., all significant values are indicated by stars. Double starred bars indicate significance levels P≤1%.
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Figure 5: Cell cycle analysis of GEP-NEN cell lines treated with siomycin AUnsynchronized BON, QGP-1, KRJ-1, LCC-18 cells were treated with 2μM siomycin A for 96h and analyzed by mitotic index flow cytometry. Cells were stained with an anti-phospho-H3 antibody and propidium iodide and analyzed versus 0.04% DMSO controls. All changes were calculated with respect to DMSO controls. A. Average of cell cycle changes in the distinct GEP-NEN cell lines after Siomycin A treatment. BON cells show a strong 72-fold increase in the sub-G1 cell death population; in KRJ-1, QGP-1 and LCC-18 cells a 5- to 9-fold increase could be detected. Most notably, the number of mitotic cells (indicated by phosphorylated histone H3) significantly decreases after siomycin A treatment in the range of 6.5- to 16-fold. B. Representative histogram of one 96h incubation experiment, blue line indicates the DMSO control, red lines visualizes the cell cycle histogram after siomycin A treatment (more detailed flow cytometry data can be found in Suppl. 2). The average chances of all cell lines under siomycin A treatment are visualized in C., all significant values are indicated by stars. Double starred bars indicate significance levels P≤1%.

Mentions: As FOXM1 is strongly associated with mitotic regulation, we wanted to understand the impact of siomycin A on the cell cycle of GEP-NEN cells. After 96h of treatment, the majority of BON, and LCC-18 and a large population of KRJ-1 cells analyzed by mitotic index flow cytometry, have undergone apoptosis or necrosis (indicated as Sub-G1) and showed a significantly decreased mitotic population (p<0.001; Figure 5). QGP-1 cells only showed a moderate increase in apoptotic or necrotic cells and an average 6-fold decrease of the mitotic cell population could be detected (Figure 5 and Suppl. 2).


FOXM1: A novel drug target in gastroenteropancreatic neuroendocrine tumors.

Briest F, Berg E, Grass I, Freitag H, Kaemmerer D, Lewens F, Christen F, Arsenic R, Altendorf-Hofmann A, Kunze A, Sänger J, Knösel T, Siegmund B, Hummel M, Grabowski P - Oncotarget (2015)

Cell cycle analysis of GEP-NEN cell lines treated with siomycin AUnsynchronized BON, QGP-1, KRJ-1, LCC-18 cells were treated with 2μM siomycin A for 96h and analyzed by mitotic index flow cytometry. Cells were stained with an anti-phospho-H3 antibody and propidium iodide and analyzed versus 0.04% DMSO controls. All changes were calculated with respect to DMSO controls. A. Average of cell cycle changes in the distinct GEP-NEN cell lines after Siomycin A treatment. BON cells show a strong 72-fold increase in the sub-G1 cell death population; in KRJ-1, QGP-1 and LCC-18 cells a 5- to 9-fold increase could be detected. Most notably, the number of mitotic cells (indicated by phosphorylated histone H3) significantly decreases after siomycin A treatment in the range of 6.5- to 16-fold. B. Representative histogram of one 96h incubation experiment, blue line indicates the DMSO control, red lines visualizes the cell cycle histogram after siomycin A treatment (more detailed flow cytometry data can be found in Suppl. 2). The average chances of all cell lines under siomycin A treatment are visualized in C., all significant values are indicated by stars. Double starred bars indicate significance levels P≤1%.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480744&req=5

Figure 5: Cell cycle analysis of GEP-NEN cell lines treated with siomycin AUnsynchronized BON, QGP-1, KRJ-1, LCC-18 cells were treated with 2μM siomycin A for 96h and analyzed by mitotic index flow cytometry. Cells were stained with an anti-phospho-H3 antibody and propidium iodide and analyzed versus 0.04% DMSO controls. All changes were calculated with respect to DMSO controls. A. Average of cell cycle changes in the distinct GEP-NEN cell lines after Siomycin A treatment. BON cells show a strong 72-fold increase in the sub-G1 cell death population; in KRJ-1, QGP-1 and LCC-18 cells a 5- to 9-fold increase could be detected. Most notably, the number of mitotic cells (indicated by phosphorylated histone H3) significantly decreases after siomycin A treatment in the range of 6.5- to 16-fold. B. Representative histogram of one 96h incubation experiment, blue line indicates the DMSO control, red lines visualizes the cell cycle histogram after siomycin A treatment (more detailed flow cytometry data can be found in Suppl. 2). The average chances of all cell lines under siomycin A treatment are visualized in C., all significant values are indicated by stars. Double starred bars indicate significance levels P≤1%.
Mentions: As FOXM1 is strongly associated with mitotic regulation, we wanted to understand the impact of siomycin A on the cell cycle of GEP-NEN cells. After 96h of treatment, the majority of BON, and LCC-18 and a large population of KRJ-1 cells analyzed by mitotic index flow cytometry, have undergone apoptosis or necrosis (indicated as Sub-G1) and showed a significantly decreased mitotic population (p<0.001; Figure 5). QGP-1 cells only showed a moderate increase in apoptotic or necrotic cells and an average 6-fold decrease of the mitotic cell population could be detected (Figure 5 and Suppl. 2).

Bottom Line: 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.

View Article: PubMed Central - PubMed

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

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.

No MeSH data available.


Related in: MedlinePlus