15-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer Cells
We previously discovered that a fat-metabolizing enzyme, 15-lipoxygenase-1 (15-LO-1), is high in human prostate cancer (PCa) and correlates with disease progression. The biologic link between the aberrant 15-LO-1/linoleic acid (LA) metabolism and fat (which is a rich source of growth factors) in PCa...
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| Format: | Article |
| Language: | English |
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Elsevier
2004-01-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558604800526 |
| _version_ | 1818835078385500160 |
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| author | Uddhav P. Kelavkar Cynthia Cohen |
| author_facet | Uddhav P. Kelavkar Cynthia Cohen |
| author_sort | Uddhav P. Kelavkar |
| collection | DOAJ |
| description | We previously discovered that a fat-metabolizing enzyme, 15-lipoxygenase-1 (15-LO-1), is high in human prostate cancer (PCa) and correlates with disease progression. The biologic link between the aberrant 15-LO-1/linoleic acid (LA) metabolism and fat (which is a rich source of growth factors) in PCa is unknown. Therefore, we tested the hypothesis that the metabolic product of the polyunsaturated fatty acid LA (i.e., 13-Shydroxyoctadecadienoic acid or 13-(S)-NODE) affects the proliferation status of PCa cells through one or more growth factors. We used parental prostate cancer cell line-3 (PC-3) and engineered PC-3 cell lines [PC3Zeo (mock-transfected), PC3-15LOS (15-LO-1-overexpressing), and PC3-15LOAS (15-LO-1-blocked)] to test our hypothesis. Of the growth factors examined, only insulin-like growth factor-1 (IGF-1) exhibited a two-fold to three-fold increase in growth response on PC315LOS cells compared to PC3-Zeo (control) cell line (P < .01). Insulin-like growth factor-1 receptor (IGF-1 R) immunohistochemical analyses of human normal and adenocarcinoma prostate tissues, as well as levels in tumors derived from nude mice injected with PC-3 cells, demonstrated that elevated IGF-1 R expression correlated with 15-LO-1 levels. Radioligand binding assays demonstrated two-fold higher IGF-1 binding sites in PC3-15LOS cells (P < .05 vs PC3-Zeo cells). IGF-1 R promoter reporter assay and affinity-purified IGF-1 R receptor levels demonstrated a four-fold higher activity in PC3-15LOS cells (P < .01 vs PC3-Zeo cells). IGF-1 R promoter activation is 13-(S)-NODE-dependent. IGF-1 R blockade with a dominant-negative adenovirus caused significant growth inhibition in PC-3 cells (P < .0001; PC3-15LOAS versus PC3-15LOS cells), as well as affected the IGF-1-stimulated mitogen-activated protein (MAP) kinase (Erki/2) and Akt activation levels. Our study suggests that overexpression of 15LO-1 in PCa contributes to the cancer progression by regulating IGF-1 R expression and activation. |
| first_indexed | 2024-12-19T02:45:00Z |
| format | Article |
| id | doaj.art-d7829b5dc4f2457e9cca04fa3ce5e30a |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-19T02:45:00Z |
| publishDate | 2004-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-d7829b5dc4f2457e9cca04fa3ce5e30a2022-12-21T20:38:57ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022004-01-0161415210.1016/S1476-5586(04)80052-615-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer CellsUddhav P. Kelavkar0Cynthia Cohen1Urological Research Laboratories, Department of Urology, University of Pittsburgh, Pittsburgh, PA, USADepartment of Pathology, Emory University, Atlanta, GA, USAWe previously discovered that a fat-metabolizing enzyme, 15-lipoxygenase-1 (15-LO-1), is high in human prostate cancer (PCa) and correlates with disease progression. The biologic link between the aberrant 15-LO-1/linoleic acid (LA) metabolism and fat (which is a rich source of growth factors) in PCa is unknown. Therefore, we tested the hypothesis that the metabolic product of the polyunsaturated fatty acid LA (i.e., 13-Shydroxyoctadecadienoic acid or 13-(S)-NODE) affects the proliferation status of PCa cells through one or more growth factors. We used parental prostate cancer cell line-3 (PC-3) and engineered PC-3 cell lines [PC3Zeo (mock-transfected), PC3-15LOS (15-LO-1-overexpressing), and PC3-15LOAS (15-LO-1-blocked)] to test our hypothesis. Of the growth factors examined, only insulin-like growth factor-1 (IGF-1) exhibited a two-fold to three-fold increase in growth response on PC315LOS cells compared to PC3-Zeo (control) cell line (P < .01). Insulin-like growth factor-1 receptor (IGF-1 R) immunohistochemical analyses of human normal and adenocarcinoma prostate tissues, as well as levels in tumors derived from nude mice injected with PC-3 cells, demonstrated that elevated IGF-1 R expression correlated with 15-LO-1 levels. Radioligand binding assays demonstrated two-fold higher IGF-1 binding sites in PC3-15LOS cells (P < .05 vs PC3-Zeo cells). IGF-1 R promoter reporter assay and affinity-purified IGF-1 R receptor levels demonstrated a four-fold higher activity in PC3-15LOS cells (P < .01 vs PC3-Zeo cells). IGF-1 R promoter activation is 13-(S)-NODE-dependent. IGF-1 R blockade with a dominant-negative adenovirus caused significant growth inhibition in PC-3 cells (P < .0001; PC3-15LOAS versus PC3-15LOS cells), as well as affected the IGF-1-stimulated mitogen-activated protein (MAP) kinase (Erki/2) and Akt activation levels. Our study suggests that overexpression of 15LO-1 in PCa contributes to the cancer progression by regulating IGF-1 R expression and activation.http://www.sciencedirect.com/science/article/pii/S147655860480052615-lipoxygenase-1 (15-LO-1)hydroxyoctadecadienoic acid (NODE)insulinlike growth factor-1 (IGF-1)insulin-like growth factor-1 receptor (IGF-1R)linoleic acid (LA) |
| spellingShingle | Uddhav P. Kelavkar Cynthia Cohen 15-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer Cells Neoplasia: An International Journal for Oncology Research 15-lipoxygenase-1 (15-LO-1) hydroxyoctadecadienoic acid (NODE) insulinlike growth factor-1 (IGF-1) insulin-like growth factor-1 receptor (IGF-1R) linoleic acid (LA) |
| title | 15-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer Cells |
| title_full | 15-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer Cells |
| title_fullStr | 15-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer Cells |
| title_full_unstemmed | 15-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer Cells |
| title_short | 15-Lipoxygenase-1 Expression Upregulates and Activates Insulin-Like Growth Factor-1 Receptor in Prostate Cancer Cells |
| title_sort | 15 lipoxygenase 1 expression upregulates and activates insulin like growth factor 1 receptor in prostate cancer cells |
| topic | 15-lipoxygenase-1 (15-LO-1) hydroxyoctadecadienoic acid (NODE) insulinlike growth factor-1 (IGF-1) insulin-like growth factor-1 receptor (IGF-1R) linoleic acid (LA) |
| url | http://www.sciencedirect.com/science/article/pii/S1476558604800526 |
| work_keys_str_mv | AT uddhavpkelavkar 15lipoxygenase1expressionupregulatesandactivatesinsulinlikegrowthfactor1receptorinprostatecancercells AT cynthiacohen 15lipoxygenase1expressionupregulatesandactivatesinsulinlikegrowthfactor1receptorinprostatecancercells |