Name:  Diane Fels

E-mail:  fels@xrt.upenn.edu

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Tumors have developed many pro-survival responses that enable them to not only survive stresses within the tumor microenvironment, but also influence tumor response to chemotherapy and radiotherapy.  For example, hypoxic tumors are more metastatic, more resistant chemotherapy and radiotherapy, and can be used as a prognostic factor for patient survival.  Tumor cells adapt to low oxygen concentrations by down regulating energy-expensive processes such as protein synthesis.  Under hypoxic stress, tumor cells activate the endoplasmic reticulum resident kinase PERK, which is responsible for phosphorylating the translation initiation factor eIF2a , thereby inhibiting protein synthesis.  The activation of PERK and eIF2a, also known as the Integrated Stress Response (ISR), constitutes one arm of a larger, coordinated ER stress program called the Unfolded Protein Response (UPR).  My project aims to determine the role of the UPR in tumor cell resistance to hypoxia.  First, we will develop methods to block PERK activity in various human cancer cell lines.  By generating tumor cells with reduced PERK activity, we will be able to determine if compromising ISR function can sensitize tumor cells to hypoxia.  Secondly, we will examine the mechanism of hypoxia-induced death using MEFs and human tumor cells with compromised PERK and eIF2a activity.  Lastly, we propose that hypoxic cancer cells, which already have an activated UPR, will be more sensitive to pharmacologic agents that induce additional ER stress, and thus such ER stressors could be useful anti-cancer agents.  The results of my project will increase our understanding of how signaling from the ER contributes to tumor cell resistance to hypoxia and may potentially offer a new strategy for targeting hypoxic cancer cells with ER stress-inducing agents.

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