Abstract
The adenoviral gene E1a is known to enhance the antitumor effect of cisplatin, one of the cornerstones of the current cancer chemotherapy. Here we study the molecular basis of E1a mediated sensitivity to cisplatin in an experimental model of Non-small cell lung cancer. Our data show how E1a blocks the induction of autophagy triggered by cisplatin and promotes the apoptotic response in resistant cells. Interestingly, at the molecular level, we present evidences showing how the phosphatase MKP1 is a major determinant of cisplatin sensitivity and its upregulation is strictly required for the induction of chemosensitivity mediated by E1a. Indeed, E1a is almost unable to promote sensitivity in H460, in which the high expression of MKP1 remains unaffected by E1a. However, in resistant cell as H1299, H23 or H661, which display low levels of MKP1, E1a expression promotes a dramatic increase in the amount of MKP1 correlating with cisplatin sensitivity. Furthermore, effective knock down of MKP1 in H1299 E1a expressing cells restores resistance to a similar extent than parental cells. In summary, the present work reinforce the critical role of MKP1 in the cellular response to cisplatin highlighting the importance of this phosphatase in future gene therapy approach based on E1a gene.
Highlights
The adenoviral protein E1a was primary described as an oncogene able to induce transformation in cooperation with other oncogenes such as Ras or Myc [1]
In order to study the E1a mediated sensitivity to cDDP we decided to use an experimental model comprised of 4 Non-small cell lung carcinoma (NSCLC) derived cell lines with different genetic backgrounds (H460, H23, H661 and H1299) [30]
We found that sensitivity associated to E1a was clear in H1299, H23 and H661 compared with H460, in which E1a associated sensitivity to cDDP was again almost marginal
Summary
The adenoviral protein E1a was primary described as an oncogene able to induce transformation in cooperation with other oncogenes such as Ras or Myc [1]. From the therapeutic point of view is well stablished that E1a is able to promote radio/chemosensitivity [6,7,8,9]. In this regard, the ability of the adenoviral protein to induce sensitivity could be explained by different mechanisms. E1a is able to block ERK1/2 activation in fibroblast in the presence of v-H-Ras by increasing the levels of MKP1, a nuclear phosphatase for MAPK, explaining the ability of E1a to escape from Ras induced senescence [20]. All the previous suggest the important role that MAPKs and protein phosphatases could play in many of the biological properties controlled by E1a
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