title: Balance between MKK6 and MKK3 mediates p38 MAPK associated resistance to cisplatin in NSCLC.
abstract: The p38 MAPK signaling pathway has been proposed as a critical mediator of the therapeutic effect of several antitumor agents, including cisplatin. Here, we found that sensitivity to cisplatin, in a system of 7 non-small cell lung carcinoma derived cell lines, correlated with high levels of MKK6 and marked activation of p38 MAPK. However, knockdown of MKK6 modified neither the response to cisplatin nor the activation of p38 MAPK. Deeper studies showed that resistant cell lines also displayed higher basal levels of MKK3. Interestingly, MKK3 knockdown significantly decreased p38 phosphorylation upon cisplatin exposure and consequently reduced the response to the drug. Indeed, cisplatin poorly activated MKK3 in resistant cells, while in sensitive cell lines MKK3 showed the opposite pattern in response to the drug. Our data also demonstrate that the low levels of MKK6 expressed in resistant cell lines are the consequence of high basal activity of p38 MAPK mediated by the elevated levels of MKK3. This finding supports the existence of a regulatory mechanism between both MAPK kinases through their MAPK. Furthermore, our results were also mirrored in head and neck carcinoma derived cell lines, suggesting our observations boast a potential universal characteristic in cancer resistance of cisplatin. Altogether, our work provides evidence that MKK3 is the major determinant of p38 MAPK activation in response to cisplatin and, hence, the resistance associated with this MAPK. Therefore, these data suggest that the balance between both MKK3 and MKK6 could be a novel mechanism which explains the cellular response to cisplatin.
authors.affiliation: Laboratorio de Oncología Molecular, Centro Regional de Investigaciones Biomédicas, PCYTA/UCLM, Albacete, Spain.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Galan-Moya
authors.forename: Miguel A
authors.initials: MA
authors.lastname: de la Cruz-Morcillo
authors.forename: Maria
authors.initials: M
authors.lastname: Llanos Valero
authors.forename: Juan L
authors.initials: JL
authors.lastname: Callejas-Valera
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar-Rojas
authors.forename: Javier
authors.initials: J
authors.lastname: Hernadez Losa
authors.forename: Mayte
authors.initials: M
authors.lastname: Salcedo
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández-Aramburo
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramon y Cajal
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sánchez-Prieto
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D048371:MAP Kinase Kinase 3 / Q000378:metabolism*; D048669:MAP Kinase Kinase 6 / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; D002945:Cisplatin