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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

Treatment of GEP-NEN cell lines with siomycin AIn three independent experiments, BON A., QGP-1 B., KRJ-1 C. and LCC-18 D. cells were treated with increasing concentrations (1μM, 2μM, 5μM) of siomycin A and (0.1μM,1μM, 5μM) everolimus for 24, 48 and 72 hours and analyzed by colorimetric proliferation assays (graphs in percent of internal DMSO controls). Siomycin A significantly inhibits GEP-NEN cell proliferation (p=0.000) and was superior to everolimus treatment in all cell lines. Antiproliferative effects could be shown for concentration ≥1μM in BON, KRJ 1, LCC 18 and ≥2μM for QGP-1 cells in relation to DMSO internal controls and were verified in a linear regression analysis. KRJ-1 cells showed a strong variance in the response due to intercellular clustering effects. Nevertheless these changes were highly significant (p=0.000). Representative data of one experiment is shown. Dotted lines indicate 100% and 10% of control.
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Figure 4: Treatment of GEP-NEN cell lines with siomycin AIn three independent experiments, BON A., QGP-1 B., KRJ-1 C. and LCC-18 D. cells were treated with increasing concentrations (1μM, 2μM, 5μM) of siomycin A and (0.1μM,1μM, 5μM) everolimus for 24, 48 and 72 hours and analyzed by colorimetric proliferation assays (graphs in percent of internal DMSO controls). Siomycin A significantly inhibits GEP-NEN cell proliferation (p=0.000) and was superior to everolimus treatment in all cell lines. Antiproliferative effects could be shown for concentration ≥1μM in BON, KRJ 1, LCC 18 and ≥2μM for QGP-1 cells in relation to DMSO internal controls and were verified in a linear regression analysis. KRJ-1 cells showed a strong variance in the response due to intercellular clustering effects. Nevertheless these changes were highly significant (p=0.000). Representative data of one experiment is shown. Dotted lines indicate 100% and 10% of control.

Mentions: We could demonstrate a significant antiproliferative effect of siomycin A on GEP-NEN cell lines p=0.000; Figure 4). Siomycin A is therefore superior even to equal doses of everolimus, which only showed significant impact on the cell lines BON (p=0.008) and LCC-18 (p=0.000), whereas QGP-1 (p=0.092) and KRJ-1 (p= 0.38) did not significantly respond to everolimus even in concentrations equal to siomycin A treatment (Figure 4).


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)

Treatment of GEP-NEN cell lines with siomycin AIn three independent experiments, BON A., QGP-1 B., KRJ-1 C. and LCC-18 D. cells were treated with increasing concentrations (1μM, 2μM, 5μM) of siomycin A and (0.1μM,1μM, 5μM) everolimus for 24, 48 and 72 hours and analyzed by colorimetric proliferation assays (graphs in percent of internal DMSO controls). Siomycin A significantly inhibits GEP-NEN cell proliferation (p=0.000) and was superior to everolimus treatment in all cell lines. Antiproliferative effects could be shown for concentration ≥1μM in BON, KRJ 1, LCC 18 and ≥2μM for QGP-1 cells in relation to DMSO internal controls and were verified in a linear regression analysis. KRJ-1 cells showed a strong variance in the response due to intercellular clustering effects. Nevertheless these changes were highly significant (p=0.000). Representative data of one experiment is shown. Dotted lines indicate 100% and 10% of control.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Treatment of GEP-NEN cell lines with siomycin AIn three independent experiments, BON A., QGP-1 B., KRJ-1 C. and LCC-18 D. cells were treated with increasing concentrations (1μM, 2μM, 5μM) of siomycin A and (0.1μM,1μM, 5μM) everolimus for 24, 48 and 72 hours and analyzed by colorimetric proliferation assays (graphs in percent of internal DMSO controls). Siomycin A significantly inhibits GEP-NEN cell proliferation (p=0.000) and was superior to everolimus treatment in all cell lines. Antiproliferative effects could be shown for concentration ≥1μM in BON, KRJ 1, LCC 18 and ≥2μM for QGP-1 cells in relation to DMSO internal controls and were verified in a linear regression analysis. KRJ-1 cells showed a strong variance in the response due to intercellular clustering effects. Nevertheless these changes were highly significant (p=0.000). Representative data of one experiment is shown. Dotted lines indicate 100% and 10% of control.
Mentions: We could demonstrate a significant antiproliferative effect of siomycin A on GEP-NEN cell lines p=0.000; Figure 4). Siomycin A is therefore superior even to equal doses of everolimus, which only showed significant impact on the cell lines BON (p=0.008) and LCC-18 (p=0.000), whereas QGP-1 (p=0.092) and KRJ-1 (p= 0.38) did not significantly respond to everolimus even in concentrations equal to siomycin A treatment (Figure 4).

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