The rapid expansion of tumor cells can result in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as cellular volume expands beyond the established vasculadty of the tissue. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis thereby preventing cellular expansion under such conditions. The ,qoalof this proposal is to determine the role of the endoplasmic reticulum stress response in sensing limitations in glucose availability and thereby facilitating cellular adaptation. Our preliminary work supports a model wherein PERK coordinates cell cycle arrest with cell survival thereby functioning as a pivotal regulator of cellular adaptation to metabolic stress. Based on our preliminary work, we hypothesize that cellular adaptation following nutrient stress depends upon the coordination of increased gene expression with decreased protein translation and that PERK functions as the central coordinator of this response. To test this hypothesis, we propose the following specific aims: 1) determine the mechanism(s) that regulates cyclin D1 protein loss following glucose deprivation; 2) determine the contribution of PERK and cyclin D1 loss to cell survival and tumor progression; 3) identification and characterization of a translation-independent effector of PERK-dependent cell survival; 4) identify genes whose expression is increased or decreased by glucose deprivation in an Nrf2-dependent manner. These studies will provide critical new insight into the mechanisms whereby the PERK protein kinase regulates cell homeostasis in response to stress. There are obvious points of cross-talk between this proposal and Project 1 as chonic ER stress is a potent inducer of apoptosis; with this project and Project 2 as hypoxia has been documented to regulate protein synthesis in a PERK-dependent and -independent manner. Through collaborations faciliated by this program, we will investigate the mechanisms whereby hypoxia (Project 2) regulates the cell cycle machinery. We will investigate how both nutrient deprivation (Project 1) and hypoxia impinge upon pro-survival signals initiated by PERK. The nature of these cooperative efforts will provide information regarding novel regulatory interactions that are subverted during neoplastic progression. The findings that revealed herein will provide the foundatioin necessary for the design of novel anti-cancer therpeutics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
United States
Zip Code
Li, Fuming; Lee, Kyoung Eun; Simon, M Celeste (2018) Detection of Hypoxia and HIF in Paraffin-Embedded Tumor Tissues. Methods Mol Biol 1742:277-282
Bansal, Ankita; Simon, M Celeste (2018) Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol 217:2291-2298
Amirian, E Susan; Ostrom, Quinn T; Armstrong, Georgina N et al. (2018) Aspirin, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-Analysis. Cancer Epidemiol Biomarkers Prev :
Ochocki, Joshua D; Khare, Sanika; Hess, Markus et al. (2018) Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity. Cell Metab 27:1263-1280.e6
Xie, Hong; Tang, Chih-Hang Anthony; Song, Jun H et al. (2018) IRE1? RNase-dependent lipid homeostasis promotes survival in Myc-transformed cancers. J Clin Invest 128:1300-1316
Ackerman, Daniel; Tumanov, Sergey; Qiu, Bo et al. (2018) Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation. Cell Rep 24:2596-2605.e5
Sanchez, Danielle J; Steger, David J; Skuli, Nicolas et al. (2018) PPAR? is dispensable for clear cell renal cell carcinoma progression. Mol Metab 14:139-149
Ricca, Jacob; Turkekul, Mesruh; Barlas, Afsar et al. (2017) Validation of Anti-Mouse PDL-1 Goat Polyclonal Antibody Staining with Mouse PDL-1 In Situ Hybridization on Adjacent Sections of Cell Pellets and Mouse Tumors. Methods Mol Biol 1554:253-262
Feng, Weiran; Jasin, Maria (2017) Homologous Recombination and Replication Fork Protection: BRCA2 and More! Cold Spring Harb Symp Quant Biol 82:329-338
Palm, Wilhelm; Araki, Jingwen; King, Bryan et al. (2017) Critical role for PI3-kinase in regulating the use of proteins as an amino acid source. Proc Natl Acad Sci U S A 114:E8628-E8636

Showing the most recent 10 out of 123 publications