Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 Action
Insulin analogs were developed to improve diabetes therapy. However, certain modifications introduced into the insulin molecule were shown to enhance their affinity to the insulin-like growth factor-1 receptor (IGF1R). Most tumors, including endometrial cancers, express high levels of IGF1R. The pre...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2018-03-01
|
| Series: | Frontiers in Endocrinology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fendo.2018.00105/full |
| _version_ | 1818110607094710272 |
|---|---|
| author | Daniel Aizen Metsada Pasmanik-Chor Rive Sarfstein Zvi Laron Ilan Bruchim Haim Werner Haim Werner |
| author_facet | Daniel Aizen Metsada Pasmanik-Chor Rive Sarfstein Zvi Laron Ilan Bruchim Haim Werner Haim Werner |
| author_sort | Daniel Aizen |
| collection | DOAJ |
| description | Insulin analogs were developed to improve diabetes therapy. However, certain modifications introduced into the insulin molecule were shown to enhance their affinity to the insulin-like growth factor-1 receptor (IGF1R). Most tumors, including endometrial cancers, express high levels of IGF1R. The present study was aimed at identifying the entire set of genes that are differentially activated by insulin glargine or detemir, in comparison to insulin and IGF1, in Type 1 and Type 2 endometrial cancer cell lines (ECC-1 and USPC-1, respectively). Global gene expression analyses demonstrated a ligand-dependent upregulated expression of filamin-A (FLNA), a gene that encodes an actin filament cross-linking protein, in both endometrial cancer cell types. Silencing experiments linked to migration assays confirmed the role of FLNA in cell growth and motility. Our data suggest that the activation of distinct sets of genes by glargine may lead to stimulation of specific pathways or, alternatively, may provide additive effects, different from those classically induced by insulin. Given that metastases are probably the main factor contributing to tumor invasiveness, the identification of FLNA as a downstream target for insulin-like hormones may be of translational relevance in oncology. Clinical studies in endometrial cancer may add further relevant information regarding the possible differential actions of insulin analogs with respect to native insulin. |
| first_indexed | 2024-12-11T02:49:50Z |
| format | Article |
| id | doaj.art-6ad62ae1395e4ee7b89d40f6b80f3a58 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-12-11T02:49:50Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Endocrinology |
| spelling | doaj.art-6ad62ae1395e4ee7b89d40f6b80f3a582022-12-22T01:23:20ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922018-03-01910.3389/fendo.2018.00105345088Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 ActionDaniel Aizen0Metsada Pasmanik-Chor1Rive Sarfstein2Zvi Laron3Ilan Bruchim4Haim Werner5Haim Werner6Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelBioinformatics Unit, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelEndocrine and Diabetes Research Unit, Schneider Children’s Medical Center, Petah Tikva, IsraelGynecological Oncology Division, Hillel Yaffe Medical Center, Technion – Israel Institute of Technology, Hadera, IsraelDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, IsraelYoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv, IsraelInsulin analogs were developed to improve diabetes therapy. However, certain modifications introduced into the insulin molecule were shown to enhance their affinity to the insulin-like growth factor-1 receptor (IGF1R). Most tumors, including endometrial cancers, express high levels of IGF1R. The present study was aimed at identifying the entire set of genes that are differentially activated by insulin glargine or detemir, in comparison to insulin and IGF1, in Type 1 and Type 2 endometrial cancer cell lines (ECC-1 and USPC-1, respectively). Global gene expression analyses demonstrated a ligand-dependent upregulated expression of filamin-A (FLNA), a gene that encodes an actin filament cross-linking protein, in both endometrial cancer cell types. Silencing experiments linked to migration assays confirmed the role of FLNA in cell growth and motility. Our data suggest that the activation of distinct sets of genes by glargine may lead to stimulation of specific pathways or, alternatively, may provide additive effects, different from those classically induced by insulin. Given that metastases are probably the main factor contributing to tumor invasiveness, the identification of FLNA as a downstream target for insulin-like hormones may be of translational relevance in oncology. Clinical studies in endometrial cancer may add further relevant information regarding the possible differential actions of insulin analogs with respect to native insulin.http://journal.frontiersin.org/article/10.3389/fendo.2018.00105/fullinsulin-like growth factor-1insulin analoguesendometrial cancermicroarray analysisfilamin-A |
| spellingShingle | Daniel Aizen Metsada Pasmanik-Chor Rive Sarfstein Zvi Laron Ilan Bruchim Haim Werner Haim Werner Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 Action Frontiers in Endocrinology insulin-like growth factor-1 insulin analogues endometrial cancer microarray analysis filamin-A |
| title | Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 Action |
| title_full | Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 Action |
| title_fullStr | Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 Action |
| title_full_unstemmed | Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 Action |
| title_short | Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 Action |
| title_sort | genome wide analyses identify filamin a as a novel downstream target for insulin and igf1 action |
| topic | insulin-like growth factor-1 insulin analogues endometrial cancer microarray analysis filamin-A |
| url | http://journal.frontiersin.org/article/10.3389/fendo.2018.00105/full |
| work_keys_str_mv | AT danielaizen genomewideanalysesidentifyfilaminaasanoveldownstreamtargetforinsulinandigf1action AT metsadapasmanikchor genomewideanalysesidentifyfilaminaasanoveldownstreamtargetforinsulinandigf1action AT rivesarfstein genomewideanalysesidentifyfilaminaasanoveldownstreamtargetforinsulinandigf1action AT zvilaron genomewideanalysesidentifyfilaminaasanoveldownstreamtargetforinsulinandigf1action AT ilanbruchim genomewideanalysesidentifyfilaminaasanoveldownstreamtargetforinsulinandigf1action AT haimwerner genomewideanalysesidentifyfilaminaasanoveldownstreamtargetforinsulinandigf1action AT haimwerner genomewideanalysesidentifyfilaminaasanoveldownstreamtargetforinsulinandigf1action |