Cisplatin is one of the most common drugs used for treatment of malignant solid tumors, including lung, head and neck, testicular and ovarian cancers. Our long range goal is to determine the molecular mechanisms underlying sensitivity to cisplatin. Recently, we determined that extracellular signal regulated kinase (ERK) provides a survival signal during treatment with cisplatin. In this proposal, we will expand our studies to examine how the other two major MAP (mitogen-activated protein) kinases, JNK and p38, along with ERK, affect sensitivity to cisplatin in lung carcinoma cell lines. Because MAP kinases are also activated in response to hypoxia, a factor that has been shown to be a determinant of response to chemotherapy, we will also examine whether the activation of the MAP kinase pathways in response to hypoxia contributes to the overall sensitivity to cisplatin. Furthermore, all three of the MAP kinases have been shown to interact with p53 and phosphorylate p53 protein. Thus, we will examine whether p53 is a mediator of either the survival signals or apoptotic signals generated by the MAP kinases in response to cisplatin treatment. The central hypothesis of this proposal is that cisplatin-induced and hypoxia-induced activation of the MAP kinase pathways leads to generation of both survival signals and apoptotic signals, the balance of which are critical in determination of cellular sensitivity to cisplatin. Furthermore, we hypothesize that the p53 pathway may be a mediator of the MAP kinase survival signals and apoptotic signals during the cellular response to cisplatin. We will test these hypotheses by: 1) elucidating the roles of the MAP kinase pathways in modulating cellular sensitivity to cisplatin in lung carcinoma cell lines; 2) examining whether activation of the MAP kinases in response to hypoxia contributes to the overall sensitivity of cells to cisplatin; 3) and by determining whether p53 mediates the survival signals or apoptotic signals generated by the MAP kinases. Identification of the molecular components that determine cisplatin sensitivity will provide novel targets for therapeutic strategies aimed at developing """"""""chemo-enhancing agents"""""""" that will provide increased efficacy of this important drug.
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