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Constantinos Koumenis, Ph.D.
Associate Professor

Koumenis

University of Pennsylvania School of Medicine
Department of Radiation Oncology
185 John Morgan Building
3620 Hamilton Walk
Philadelphia, PA 19104-6072
Office: (215) 898-0076
Lab: (215) 898-0078
Fax: (215)-898-0090
koumenis@xrt.upenn.edu

Publications
Koumenis Lab
Costas Koumenis CV

Research Interests

The goal of my laboratory is twofold: (a) To understand the mechanisms by which components of the microenvironment (e.g. hypoxia) interact with cellular survival/apoptotic pathways to produce a more resistant tumor phenotype. (b) To exploit the unique features of the tumor microenvironment for the design of tumor-specific therapeutic strategies.

Low oxygen tension (hypoxia-anoxia) in tumors occurs when the rate of tumor growth outpaces that of new blood vessel formation (angiogenesis). Hypoxic tumors are more metastatic, more resistant to radiotherapy and chemotherapy and poor tumor oxygenation is an independent predictor of lower patient survival. It is hypothesized that the mechanisms that enable tumor cells to adapt to this stringent environment also contribute to their resistant and aggressive nature. Cells adapt to low oxygen conditions by decreasing the rate of energy-consuming processes, most notably macromolecular synthesis. However, the molecular mechanisms employed by tumor cells to regulate protein synthesis are not yet known. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2α on ser51, which leads to inhibition of protein synthesis.

My lab has shown that cells exposed to hypoxia upregulate phosphorylation of eIF2α, a modification which was readily reversed upon reoxygenation and which is required for downregulation of protein synthesis under hypoxia. By using biochemical and genetic means, we have also identified the endoplasmic reticulum resident PERK, as the kinase primarily responsible for this modification. PERK-/- MEFs fail to phosphorylate eIF2α and exhibit lower survival after prolonged exposure to hypoxia compared with wt-fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2α and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the Unfolded Protein Response (UPR) (see Fig.1)

regulation of translation by hypoxia unfolded protein response
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We are now focusing our efforts in characterizing other aspects of the Unfolded Protein Response under hypoxic stress, primarily activation of UPR-specific gene expression and induction of apoptosis through Caspase-7 and Caspase-12 cleavage. Our current model (see Fig.2) suggests that under mild or transient hypoxia, the adaptive responses of eIF2α phosphorylation and transcriptional activation through ATF6 and XBP promote cell survival, while at more stringent hypoxia-anoxia or prolonged hypoxic conditions, the apoptotic pathway is activated. The model also suggests that inhibition of the adaptive responses should “push” the UPR more into the apoptotic pathway, an approach that could have therapeutic implications for hypoxia-specific therapies.

Selected Publications

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