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Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase.
Cancer Res. 2001 Feb 15; 61(4):1367-74.CR

Abstract

Elevated levels of urokinase plasminogen activator-1 (uPA) and the insulin-like growth factor-I receptor (IGF-IR) are associated with breast cancer recurrence and decreased survival. It is possible that activation of IGF-IR and elevations in uPA are mechanistically linked. Our laboratory recently showed that insulin-like growth factor-I (IGF-I) induces uPA protein and mRNA in the breast cancer cell line MDA-MB-231. We also found that IGF-IR and uPA were commonly overexpressed in primary breast cancers. In this study, we investigated the signal transduction pathway through which IGF-I regulates uPA. Phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p70 kinase were inhibited with LY294002, PD98059, and rapamycin, respectively. Induction of uPA protein by IGF-I was partially inhibited by LY294002 (60% inhibition) or PD98059 (30% inhibition) but not by rapamycin. The production of uPA protein induced by IGF-I was blocked up to 90% by the tyrosine kinase inhibitor herbimycin A. Furthermore, herbimycin A suppressed the phosphorylation of AKT and Erk1/2. Next, we tested the impact of the signal transduction inhibitors on uPA gene expression. Both LY294002 and PD98059 were required to completely inhibit uPA mRNA expression, whereas each drug alone resulted in approximately 50% reduction in uPA expression. Next, using a minimal uPA-luciferase promoter construct containing the binding sites for the AP-1 and Ets transcription factors, we observed that IGF-I stimulated the uPA promoter via these sites. Furthermore, both Ly294002 and PD98059 were necessary to block IGF-I-stimulated uPA-Luc activity. In summary, we conclude that IGF-I requires both phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase-dependent pathways to optimally induce uPA expression. These findings suggest that the development of drugs targeting these pathways may benefit breast cancer patients at a high risk of recurrence, such as those who have primary tumors overexpressing IGF-IR and uPA.

Authors+Show Affiliations

National Cancer Institute, NIH, Research, Triangle Park, North Carolina 27709, USA. SandraE_Dunn@NCSU.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

11245436

Citation

Dunn, S E., et al. "Up-regulation of Urokinase-type Plasminogen Activator By Insulin-like Growth factor-I Depends Upon Phosphatidylinositol-3 Kinase and Mitogen-activated Protein Kinase Kinase." Cancer Research, vol. 61, no. 4, 2001, pp. 1367-74.
Dunn SE, Torres JV, Oh JS, et al. Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase. Cancer Res. 2001;61(4):1367-74.
Dunn, S. E., Torres, J. V., Oh, J. S., Cykert, D. M., & Barrett, J. C. (2001). Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase. Cancer Research, 61(4), 1367-74.
Dunn SE, et al. Up-regulation of Urokinase-type Plasminogen Activator By Insulin-like Growth factor-I Depends Upon Phosphatidylinositol-3 Kinase and Mitogen-activated Protein Kinase Kinase. Cancer Res. 2001 Feb 15;61(4):1367-74. PubMed PMID: 11245436.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase. AU - Dunn,S E, AU - Torres,J V, AU - Oh,J S, AU - Cykert,D M, AU - Barrett,J C, PY - 2001/3/14/pubmed PY - 2001/4/3/medline PY - 2001/3/14/entrez SP - 1367 EP - 74 JF - Cancer research JO - Cancer Res VL - 61 IS - 4 N2 - Elevated levels of urokinase plasminogen activator-1 (uPA) and the insulin-like growth factor-I receptor (IGF-IR) are associated with breast cancer recurrence and decreased survival. It is possible that activation of IGF-IR and elevations in uPA are mechanistically linked. Our laboratory recently showed that insulin-like growth factor-I (IGF-I) induces uPA protein and mRNA in the breast cancer cell line MDA-MB-231. We also found that IGF-IR and uPA were commonly overexpressed in primary breast cancers. In this study, we investigated the signal transduction pathway through which IGF-I regulates uPA. Phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p70 kinase were inhibited with LY294002, PD98059, and rapamycin, respectively. Induction of uPA protein by IGF-I was partially inhibited by LY294002 (60% inhibition) or PD98059 (30% inhibition) but not by rapamycin. The production of uPA protein induced by IGF-I was blocked up to 90% by the tyrosine kinase inhibitor herbimycin A. Furthermore, herbimycin A suppressed the phosphorylation of AKT and Erk1/2. Next, we tested the impact of the signal transduction inhibitors on uPA gene expression. Both LY294002 and PD98059 were required to completely inhibit uPA mRNA expression, whereas each drug alone resulted in approximately 50% reduction in uPA expression. Next, using a minimal uPA-luciferase promoter construct containing the binding sites for the AP-1 and Ets transcription factors, we observed that IGF-I stimulated the uPA promoter via these sites. Furthermore, both Ly294002 and PD98059 were necessary to block IGF-I-stimulated uPA-Luc activity. In summary, we conclude that IGF-I requires both phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase-dependent pathways to optimally induce uPA expression. These findings suggest that the development of drugs targeting these pathways may benefit breast cancer patients at a high risk of recurrence, such as those who have primary tumors overexpressing IGF-IR and uPA. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/11245436/Up_regulation_of_urokinase_type_plasminogen_activator_by_insulin_like_growth_factor_I_depends_upon_phosphatidylinositol_3_kinase_and_mitogen_activated_protein_kinase_kinase_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11245436 DB - PRIME DP - Unbound Medicine ER -