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.

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

“…Similar to cyclophilin overexpression in cancer, an increase in p38MAPK phosphorylation has also been found in different tumours, which in turn correlates with poor prognosis and resistance to cisplatin treatment. 9,10,25,27 Considering the strong correlation among p38MAPK, cyclophilins and sensitivity to cisplatin, we next speculated that p38-dependent sensitivity of tumour cells to cisplatin could be, at least in part, mediated through CypAdependent isomerisation of Pro224.…”

A Possible Mechanism of Cisplatin-Induced Tumor Necrosis Factor (TNF)-α Production in Murine Macrophages

“…Several studies have shown that ROS leads to increases in the phosphorylation of ERK and p38 MAPK [26][27][28]. Cisplatin generates hydrogen peroxide (H 2 O 2 ), a relatively long-lived species of ROS, in a variety of cells including macrophages [29,30].…”

Mitogen-Activated Protein Kinase Signal Transduction in Solid Tumors

“…For the NSCLC, in which EGFR exhibits overexpression or aberrant activation in 50-90% of cancer cells (Larsen and Minna, 2011), Eva M. Galan-Moya et al demonstrated by innovatively using transformed cell lines that the interplay between MAPKKs was crucial for p38 MAPK activation in response to cDDP (Cisplatin) and proposed that the imbalance between MKK6 and MKK3 could be a potential biomarker for NSCLL, while MKK3, but not MKK6, was the critical player, although MKK3 controls MKK6 levels in NSCLC derived cell lines through activation of p38 MAPK (Galan-Moya et al, 2011).…”