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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

Role of STAT3 expressionA. Primary tumor samples were lysed, analyzed by western blot in three independent experiments and densitometrically assessed. Statistical evaluation was done by linear multivariable regression and by non-parametric Mann-Whitney U Test, respectively. On tissue level, FOXM1 expression strongly correlated with STAT3 expression (R square= 0.823, adjusted R square=0.816) by linear regression. STAT3 is therefore associated with FOXM1 expression. A tendency of both proteins to be expressed to a higher extent in metastasis, compared to primary tumor material can be assumed, but requires a larger number of tumor samples. B. BON, QGP-1 and LCC-18 cell lines were treated with 2 and 3.5μM siomycin A for 72h. Cells were lysed and lysates were prepared by western blot. Immunodetection of STAT3 showed a strong decrease of STAT3 expression after siomycin A treatment in all cell lines.
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Figure 2: Role of STAT3 expressionA. Primary tumor samples were lysed, analyzed by western blot in three independent experiments and densitometrically assessed. Statistical evaluation was done by linear multivariable regression and by non-parametric Mann-Whitney U Test, respectively. On tissue level, FOXM1 expression strongly correlated with STAT3 expression (R square= 0.823, adjusted R square=0.816) by linear regression. STAT3 is therefore associated with FOXM1 expression. A tendency of both proteins to be expressed to a higher extent in metastasis, compared to primary tumor material can be assumed, but requires a larger number of tumor samples. B. BON, QGP-1 and LCC-18 cell lines were treated with 2 and 3.5μM siomycin A for 72h. Cells were lysed and lysates were prepared by western blot. Immunodetection of STAT3 showed a strong decrease of STAT3 expression after siomycin A treatment in all cell lines.

Mentions: The strong correlation of FOXM1 and STAT3 expression could be confirmed in lysates obtained from frozen primary and metastasis tumor material of GEP-NEN patients. Here, FOXM1 was significantly associated with STAT3 expression (p=0.000; Figure 2A). We could further detect a tendency of FOXM1 and STAT3 to be higher expressed in the metastasis group of tumor tissue than in the primary tumor group (Figure 2). We therefore show that STAT3 and FOXM1 in GEP-NENs may have prognostic significance.


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)

Role of STAT3 expressionA. Primary tumor samples were lysed, analyzed by western blot in three independent experiments and densitometrically assessed. Statistical evaluation was done by linear multivariable regression and by non-parametric Mann-Whitney U Test, respectively. On tissue level, FOXM1 expression strongly correlated with STAT3 expression (R square= 0.823, adjusted R square=0.816) by linear regression. STAT3 is therefore associated with FOXM1 expression. A tendency of both proteins to be expressed to a higher extent in metastasis, compared to primary tumor material can be assumed, but requires a larger number of tumor samples. B. BON, QGP-1 and LCC-18 cell lines were treated with 2 and 3.5μM siomycin A for 72h. Cells were lysed and lysates were prepared by western blot. Immunodetection of STAT3 showed a strong decrease of STAT3 expression after siomycin A treatment in all cell lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Role of STAT3 expressionA. Primary tumor samples were lysed, analyzed by western blot in three independent experiments and densitometrically assessed. Statistical evaluation was done by linear multivariable regression and by non-parametric Mann-Whitney U Test, respectively. On tissue level, FOXM1 expression strongly correlated with STAT3 expression (R square= 0.823, adjusted R square=0.816) by linear regression. STAT3 is therefore associated with FOXM1 expression. A tendency of both proteins to be expressed to a higher extent in metastasis, compared to primary tumor material can be assumed, but requires a larger number of tumor samples. B. BON, QGP-1 and LCC-18 cell lines were treated with 2 and 3.5μM siomycin A for 72h. Cells were lysed and lysates were prepared by western blot. Immunodetection of STAT3 showed a strong decrease of STAT3 expression after siomycin A treatment in all cell lines.
Mentions: The strong correlation of FOXM1 and STAT3 expression could be confirmed in lysates obtained from frozen primary and metastasis tumor material of GEP-NEN patients. Here, FOXM1 was significantly associated with STAT3 expression (p=0.000; Figure 2A). We could further detect a tendency of FOXM1 and STAT3 to be higher expressed in the metastasis group of tumor tissue than in the primary tumor group (Figure 2). We therefore show that STAT3 and FOXM1 in GEP-NENs may have prognostic significance.

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