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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

Western blot analysis of FOXM1 and potential target expression in GEP-NEN cell linesAll cell lines including the non-neuroendocrine HT-29 and the FOXM1 overexpressing U2OS control cell lines expressed FOXM1 A. KRJ-1 cells, which is the only wild type TP53 GEP-NEN cell line in this study (unpublished data) expressed the lowest level of FOXM1. After short time (12h) treatment with 10μM siomycin A, an increase of p21 expression was detected in a time-dependent manner B. Treatment of synchronized GEP-NEN cell lines with 2 and 3.5μM siomycin A for 72 hours resulted in a decrease of FOXM1, chromogranin A, aurora A and survivin expression C. Dependency of chromogranin A and aurora A down-regulation from FOXM1 depletion could be verifed by RNA interference with two different siRNAs targeting FOXM1 mRNA D. in BON and QGP-1 cells. Treatment with 2μM everolimus for 72 hours did not remarkably reduce FOXM1 expression E.
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Figure 3: Western blot analysis of FOXM1 and potential target expression in GEP-NEN cell linesAll cell lines including the non-neuroendocrine HT-29 and the FOXM1 overexpressing U2OS control cell lines expressed FOXM1 A. KRJ-1 cells, which is the only wild type TP53 GEP-NEN cell line in this study (unpublished data) expressed the lowest level of FOXM1. After short time (12h) treatment with 10μM siomycin A, an increase of p21 expression was detected in a time-dependent manner B. Treatment of synchronized GEP-NEN cell lines with 2 and 3.5μM siomycin A for 72 hours resulted in a decrease of FOXM1, chromogranin A, aurora A and survivin expression C. Dependency of chromogranin A and aurora A down-regulation from FOXM1 depletion could be verifed by RNA interference with two different siRNAs targeting FOXM1 mRNA D. in BON and QGP-1 cells. Treatment with 2μM everolimus for 72 hours did not remarkably reduce FOXM1 expression E.

Mentions: In our preliminary experiments, we have demonstrated that FOXM1 is expressed in GEP-NENs to a high extent and can be correlated to differentiation and the occurrence of metastasis in gastrointestinal NEN. Until now, effective therapy options for these tumors are not available. We therefore analyzed the effect of proteasome inhibitors, which target FOXM1 [28-31], in vitro. To initiate our studies, we assessed the basal expression of FOXM1 in the GEP NEN cell lines BON, QGP-1, KRJ-1, LCC-18 by western blot. All cell lines expressed detectable levels of FOXM1 (Figure 3A).


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)

Western blot analysis of FOXM1 and potential target expression in GEP-NEN cell linesAll cell lines including the non-neuroendocrine HT-29 and the FOXM1 overexpressing U2OS control cell lines expressed FOXM1 A. KRJ-1 cells, which is the only wild type TP53 GEP-NEN cell line in this study (unpublished data) expressed the lowest level of FOXM1. After short time (12h) treatment with 10μM siomycin A, an increase of p21 expression was detected in a time-dependent manner B. Treatment of synchronized GEP-NEN cell lines with 2 and 3.5μM siomycin A for 72 hours resulted in a decrease of FOXM1, chromogranin A, aurora A and survivin expression C. Dependency of chromogranin A and aurora A down-regulation from FOXM1 depletion could be verifed by RNA interference with two different siRNAs targeting FOXM1 mRNA D. in BON and QGP-1 cells. Treatment with 2μM everolimus for 72 hours did not remarkably reduce FOXM1 expression E.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Western blot analysis of FOXM1 and potential target expression in GEP-NEN cell linesAll cell lines including the non-neuroendocrine HT-29 and the FOXM1 overexpressing U2OS control cell lines expressed FOXM1 A. KRJ-1 cells, which is the only wild type TP53 GEP-NEN cell line in this study (unpublished data) expressed the lowest level of FOXM1. After short time (12h) treatment with 10μM siomycin A, an increase of p21 expression was detected in a time-dependent manner B. Treatment of synchronized GEP-NEN cell lines with 2 and 3.5μM siomycin A for 72 hours resulted in a decrease of FOXM1, chromogranin A, aurora A and survivin expression C. Dependency of chromogranin A and aurora A down-regulation from FOXM1 depletion could be verifed by RNA interference with two different siRNAs targeting FOXM1 mRNA D. in BON and QGP-1 cells. Treatment with 2μM everolimus for 72 hours did not remarkably reduce FOXM1 expression E.
Mentions: In our preliminary experiments, we have demonstrated that FOXM1 is expressed in GEP-NENs to a high extent and can be correlated to differentiation and the occurrence of metastasis in gastrointestinal NEN. Until now, effective therapy options for these tumors are not available. We therefore analyzed the effect of proteasome inhibitors, which target FOXM1 [28-31], in vitro. To initiate our studies, we assessed the basal expression of FOXM1 in the GEP NEN cell lines BON, QGP-1, KRJ-1, LCC-18 by western blot. All cell lines expressed detectable levels of FOXM1 (Figure 3A).

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