Activation of Cdc2 contributes to apoptosis in HPV E6 expressing human keratinocytes in response to therapeutic agents Free

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Infection with human papillomaviruses (HPV) is strongly associated with the development of cervical cancer. The HPV E6 induces cell proliferation and apoptosis in cervical cancer precursor lesions. Although inactivation of the tumor suppressor p53 plays an important role for E6 to promote cell growth, the molecular basis of E6-induced apoptosis is poorly understood. While it is expected that inactivation of p53 by E6 should lead to a reduction in apoptosis, numerous studies demonstrated that E6 could in fact sensitize cells to apoptosis. In the present study, we demonstrated that expression of E6 in human keratinocytes rendered sensitization to chemotherapeutic agents. The cell death was shown to be apoptosis involving caspase activation and the mitochondria pathway. To explore mechanisms involved in sensitization of E6 expressing cells to apoptosis, we used a proteomic approach to identify proteins differentially expressed in E6 expressing and control keratinocytes. Among nearly a thousand proteins examined, Cdc2 was demonstrated to be the most dramatically up-regulated protein in E6 expressing cells and was therefore further characterized. Using genetic, pharmacologic, and siRNA strategy, a role of Cdc2 in E6 expression-conferred apoptosis was demonstrated. Thus these results have important therapeutic implications in enhancing the efficacy of chemotherapy.