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MKP1 repression is required for the chemosensitizing effects of NF-kappaB and PI3K inhibitors to cisplatin in non-small cell lung cancer.
- Source :
-
Cancer letters [Cancer Lett] 2009 Dec 28; Vol. 286 (2), pp. 206-16. Date of Electronic Publication: 2009 Jun 23. - Publication Year :
- 2009
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7980
- Volume :
- 286
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer letters
- Publication Type :
- Academic Journal
- Accession number :
- 19553005
- Full Text :
- https://doi.org/10.1016/j.canlet.2009.05.029