MKP1/CL100 controls tumor growth and sensitivity to cisplatin in non-small-cell lung cancer.
Non-small-cell lung cancer (NSCLC) represents the most frequent and therapy-refractive sub-class of lung cancer. Improving apoptosis induction in NSCLC represents a logical way forward in treating this tumor. Cisplatin, a commonly used therapeutic agent in NSCLC, induces activation of N-terminal-c-Jun kinase (JNK) that, in turn, mediates induction of apoptosis. In analysing surgical tissue samples of NSCLC, we found that expression of MKP1/CL100, a negative regulator of JNK, showed a strong nuclear staining for tumor cells, whereas, in normal bronchial epithelia, MKP1 was localized in the cytoplasm as well as in nuclei. In the NSCLC-derived cell lines H-460 and H-23, we found that MKP1 was constitutively expressed. Expressing a small-interfering RNA (siRNA) vector for MKP1 in H-460 cells resulted in a more efficient activation by cisplatin of JNK and p38 than in the parental cells, and this correlated with a 10-fold increase in sensitivity to cisplatin. A similar response was also observed in H-460 and H-23 cells when treated with the MKP1 expression inhibitor RO-31-8220. Moreover, expression of a siRNA-MKP2, an MKP1-related phosphatase, had no effect on H-460 cell viability response to cisplatin. Tumors induced by H-460 cells expressing MKP1 siRNA grew slower in nu(-)/nu(-) mice and showed more susceptibility to cisplatin than parental cells, and resulted in an impaired growth of the tumor in mice. On the other hand, overexpression of MKP1 in the H-1299 NSCLC-derived cell line resulted in further resistance to cisplatin. Overall, the results showed that inhibition of MKP1 expression contributes to a slow down in cell growth in mice and an increase of cisplatin-induced cell death in NSCLC. As such, MKP1 can be an attractive target in sensitizing cells to cisplatin to increase the effectiveness of the drug in treating NSCLC.
Chattopadhyay
S
S
Translational Oncology Unit CSIC/UAM, Instituto de Investigaciones Biomédicas, C/Arturo Duperier, Madrid, Spain.
Machado-Pinilla
R
R
Manguan-García
C
C
Belda-Iniesta
C
C
Moratilla
C
C
Cejas
P
P
Fresno-Vara
J A
JA
de Castro-Carpeño
J
J
Casado
E
E
Nistal
M
M
Gonzalez-Barón
M
M
Perona
R
R
D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D054638:Dual Specificity Phosphatase 1; D005260:Female; D006131:Growth Inhibitors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D006131:Growth Inhibitors; D017874:Immediate-Early Proteins; D034741:RNA, Small Interfering; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; D002945:Cisplatin