1. MKP1 repression is required for the chemosensitizing effects of NF-kappaB and PI3K inhibitors to cisplatin in non-small cell lung cancer.
- Author
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Cortes-Sempere M, Chattopadhyay S, Rovira A, Rodriguez-Fanjul V, Belda-Iniesta C, Tapia M, Cejas P, Machado-Pinilla R, Manguan-García C, Sánchez-Pérez I, Nistal M, Moratilla C, de Castro-Carpeño J, Gonzalez-Barón M, Albanell J, and Perona R
- Subjects
- Antineoplastic Agents pharmacology, Blotting, Western, Boronic Acids pharmacology, Bortezomib, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung metabolism, Cell Line, Tumor, Cell Survival drug effects, Chromones pharmacology, Dual Specificity Phosphatase 1 genetics, Humans, Immunohistochemistry, JNK Mitogen-Activated Protein Kinases metabolism, Lung Neoplasms genetics, Lung Neoplasms metabolism, Morpholines pharmacology, NF-kappa B antagonists & inhibitors, Nitriles pharmacology, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation drug effects, Proto-Oncogene Proteins c-akt metabolism, Pyrazines pharmacology, RNA Interference, Signal Transduction drug effects, Sulfones pharmacology, Carcinoma, Non-Small-Cell Lung pathology, Cisplatin pharmacology, Dual Specificity Phosphatase 1 metabolism, Lung Neoplasms pathology, NF-kappa B metabolism, Phosphatidylinositol 3-Kinases metabolism
- Abstract
Treatment of non-small cell lung cancer (NSCLC) with cisplatin has a level of antitumor activity still modest. We have shown previously that MKP1/DUSP1 inhibits cisplatin-induced apoptosis in NSCLC cells and is overexpressed in tumors from most patients with stage I-II NSCLC. Here, using different NSCLC cell lines we found that MKP1 and NF-kappaB are differentially expressed. We studied whether targeting MKP1, NF-kappaB or both affects cisplatin-induced cell death. MKP1 is expressed in H460 and H727 cells. H727 and H1299 cells showed constitutive phosphorylation of Akt and increased NF-kappaB activity than did H460 cells. H460-MKP1-siRNA-expressing cells (but not H727-MKP1-siRNA or H1299-MKP1-siRNA cells) exhibit a marked increase in cisplatin response compared with parental cells. Treatment with the PI3K inhibitor LY294002 or the NF-kappaB inhibitor BAY11-7082 enhanced cisplatin antitumor activity in parental H1299 cells but only weakly affected responses of H727 and H460 cells. MKP1-siRNA expression enhanced the chemosensitization effect of LY294002 and BAY11-7082 on H727 and H460 cells. Additionally, NSCLC cell lines with higher NF-kappaB-constitutive activation were the most sensitive to PS-341 (Bortezomib), a non-specific NF-kappaB inhibitor. This finding suggests the proteasome as a suitable strategy in treating NSCLC tumors with high constitutive NF-kappaB activity. Altogether, these results showed that either an activated PI3K/Akt/NF-kappaB pathway and/or high MKP1 was linked to reduced sensitivity to cisplatin in NSCLC cells. Inhibition of NF-kappaB or PI3K potently enhanced cisplatin cytotoxicity in cells with endogenous or genetically induced low MKP1 levels. These findings support the potential improvement in cisplatin responses by co-targeting NF-kappaB or Akt and MKP1.
- Published
- 2009
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