p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma cells
| Autor: | Yu-Tzu Tai, Dharminder Chauhan, Noopur Raje, Teru Hideshima, Paul G. Richardson, Klaus Podar, Kenji Ishitsuka, Nikhil C. Munshi, Mitsiades Constantine S, Kenneth C. Anderson, Makoto Hamasaki, Linda S. Higgins, Hiromasa Hideshima, Tony A. Navas, George Schreiner, Aaron N. Nguyen |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
MAPK/ERK pathway
Cancer Research p38 mitogen-activated protein kinases Immunology Down-Regulation Antineoplastic Agents Biology Biochemistry p38 Mitogen-Activated Protein Kinases Bortezomib chemistry.chemical_compound Hsp27 Downregulation and upregulation Heat shock protein Cell Line Tumor Genetics medicine Humans Protein kinase A Molecular Biology Heat-Shock Proteins Kinase Cell Biology Hematology Boronic Acids chemistry Pyrazines Cancer research biology.protein Growth inhibition Multiple Myeloma medicine.drug |
| Zdroj: | Oncogene. 23:8766-8776 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/sj.onc.1208118 |
| Popis: | PS-341 (pyrazylcarbonyl-Phe-Leu-boronate, bortezomib, Velcade™) represents a class of peptide boronate proteasome inhibitors which inhibit 26S proteasome activity, and demonstrated promise as potential novel anti-cancer therapies. PS-341: induces heat shock proteins (Hsps); activates JNK; induces apoptosis in MM cells mediated by activation of caspase-8, -9, and -3; induces cleavage of DNA protein kinase catalytic subunit (DNA-PKcs) and ATM; overcomes conventional drug resistance conferred by IL-6 or adherence to bone marrow stromal cells (BMSCs); and further abrogates IL-6-triggered signaling cascades by caspase-dependent downregulation of gp130 (CD130). Importantly, a phase II clinical trial of Velcade in refractory relapsed MM demonstrated 35% responses, including 10% complete and near complete responses; however, 65% of patients did not respond to PS-341. We have previously shown that heat shock protein (Hsp)27 is upregulated after PS-341 treatment, that overexpression of Hsp27 confers PS-341 resistance, and that inhibition of Hsp27 overcomes PS-341 resistance. Since Hsp27 is a downstream target of p38 mitogen-activated protein kinase (MAPK)/ MAPK-mitogen-activated protein kinase-2 (MAPKAPK2), we hypothesized that inhibition of p38 MAPK activity could augment PS-341 cytotoxicity by downregulating Hsp27. Although p38 MAPK inhibitor SCIO-469 (Scios Inc, CA) alone did not induce significant growth inhibition in MM.1S cells, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK, as well as upregulation of Hsp27, associated with enhanced cytotoxicity. Importantly, SCIO-469 enhanced phosphorylation of c-Jun NH2-terminal kinase (JNK) and augmented cleavage of caspase-8 and poly (ADP)-ribose polymerase (PARP). Moreover, SCIO-469 downregulated PS-341-induced increases in G2/M phase cells, associated with downregulation of p21Cip1 expression. These results were further confirmed using transient transfection with p38 MAPK siRNA. Importantly, SCIO-469 treatment augmented cytotoxicity of PS-341 even against PS-341 resistant cell lines and patient MM cells. These studies therefore provide the framework for clinical trials of SCIO-469 to enhance sensitivity and overcome resistance to PS-341, thereby improving patient outcome in MM. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|