Inhibition of HER-kinase activation prevents ERK-mediated degradation of PPARγ
| Autor: | William D. Fox, Desheng Lu, Michael Hedvat, Stuart Holden, David B. Agus, Ganghua Huang, Dennis A. Carson, Lorenzo M. Leoni, Maripat Corr, Anjali Jain |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
CD36 Antigens
Male MAPK/ERK pathway Cancer Research Time Factors Receptors Cytoplasmic and Nuclear Pharmacology Monocytes Mice 0302 clinical medicine Protein Isoforms Cyclin D1 Coloring Agents Receptor 0303 health sciences Reverse Transcriptase Polymerase Chain Reaction Kinase Transfection Flow Cytometry ErbB Receptors Oncology 030220 oncology & carcinogenesis Mitogen-Activated Protein Kinases Transcriptional Activation MAP Kinase Signaling System Blotting Western Down-Regulation Mice Nude Antineoplastic Agents Protein degradation Biology Models Biological Cell Line 03 medical and health sciences Enzyme activator Downregulation and upregulation Cell Line Tumor Animals Humans 030304 developmental biology Prostatic Neoplasms Cell Biology Lipid Metabolism Enzyme Activation Models Chemical NIH 3T3 Cells Cancer research Etodolac Azo Compounds Neoplasm Transplantation Transcription Factors |
| Zdroj: | Cancer Cell. 5:565-574 |
| ISSN: | 1535-6108 |
| DOI: | 10.1016/j.ccr.2004.05.014 |
| Popis: | R-etodolac, a nonsteroidal anti-inflammatory drug, inhibits the progression of CWRSA6 androgen-independent and LuCaP-35 androgen-dependent prostate cancer xenograft growth through downregulation of cyclin D1 expression via the PPARgamma pathway. PPARgamma protein degradation, observed post-R-etodolac treatment, resulted from phospho-MAP kinase (p44/42) induction by R-etodolac negatively regulating PPARgamma function. Negative regulation of PPARgamma was overcome by a combination regimen of R-etodolac with the HER-kinase axis inhibitor, rhuMab 2C4, which demonstrated an additive antitumor effect. We further show that the inhibition of HER-kinase activity by rhuMab 2C4 is sufficient to inhibit PPARgamma protein degradation. This study introduces a novel concept of an in vivo crosstalk between the HER-kinase axis and PPARgamma pathways, ultimately leading to negative regulation of PPARgamma activity and tumor growth inhibition. |
| Databáze: | OpenAIRE |
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