Rapidly proliferating cancer cells must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limiting as tumor volume expands beyond the established vascularity of the tissue. In normal cells, limits in nutrient availability trigger growth arrest and/or apoptosis thereby preventing cellular expansion under such conditions. The goal of this proposal is to determine the role of the endoplasmic reticulum stress response/Unfolded Protein Response (UPR) in sensing limitations in glucose availability and thereby facilitating cellular adaptation. PERK, one of three proximal signal transducers of the UPR plays a central role in mediating cell fate decisions. The pro-survival function of PERK has garnered it considerable interest from the point of view of developing small molecule inhibitors of its catalytic activity and the hope that such inhibitors would have potent anti-tumor activity. Indeed, in the previous funding cycle, we demonstrated that PERK inhibition is of potential clinical benefit in metastatic breast cancer. However, because PERK also pro-apoptotic and anti-proliferative activities, it could also exhibit tumor suppressive activity. Central our ability to effectively target PERK is a complete understanding of both its anti-proliferative/pro-apoptotic as well as pro-survival functions. In our preliminary work, we provide evidence that while PERK functions to facilitate melanoma progression, it paradoxically functions as a potent suppressor of melanoma initiation. In this proposal, we describe three integrated aims that focus on the elucidation of PERK function in melanoma initiation (Aim 1), the potential efficacy of anti-PERK targeted therapy (Aim 2) and the identification of tumor-derived PERK mutants and their role in tumor initiation/progression (Aim 3). These studies will provide critical new insight into the mechanisms whereby the PERK protein kinase regulates cell homeostasis in response to stress.
The aims i nterface with Projects 1 and 2 through common interests in signaling pathways that sense and respond to metabolic limitation and through response and regulation of lipid metabolism. The findings steming from work proposed herein will provide a foundation for the design of novel anti-cancer therpeutics.

Public Health Relevance

Recent work has revealed that inactivation of PERK can promote tumor progression providing support for the development of small molecule inhibitors of PERK for cancer treatment. However, our preliminary data also reveal potential tissue specific tumor suppressive properties of PERK highlighting the limited nature of our understanding of PERK regulation of cell fate. The work described in this Project will delineate molecular mechanisms of both pro- and anti-tumor properties of PERK using both chemical and genetic approaches.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA104838-11
Application #
8742522
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2003-12-01
Project End
2019-08-31
Budget Start
2014-09-17
Budget End
2015-08-31
Support Year
11
Fiscal Year
2014
Total Cost
$261,383
Indirect Cost
$63,203
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Rozpedek, W; Pytel, D; Mucha, B et al. (2016) The Role of the PERK/eIF2α/ATF4/CHOP Signaling Pathway in Tumor Progression During Endoplasmic Reticulum Stress. Curr Mol Med 16:533-44
Krishna, Shefali; Palm, Wilhelm; Lee, Yongchan et al. (2016) PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following Engulfment. Dev Cell 38:536-47
Tschaharganeh, Darjus F; Lowe, Scott W; Garippa, Ralph J et al. (2016) Using CRISPR/Cas to study gene function and model disease in vivo. FEBS J 283:3194-203
Pavlova, Natalya N; Thompson, Craig B (2016) The Emerging Hallmarks of Cancer Metabolism. Cell Metab 23:27-47
Xu, Zhenhua; Bu, Yiwen; Chitnis, Nilesh et al. (2016) miR-216b regulation of c-Jun mediates GADD153/CHOP-dependent apoptosis. Nat Commun 7:11422
Pytel, D; Majsterek, I; Diehl, J A (2016) Tumor progression and the different faces of the PERK kinase. Oncogene 35:1207-15
Gade, Terence P F; Hunt, Stephen J; Harrison, Neil et al. (2015) Segmental Transarterial Embolization in a Translational Rat Model of Hepatocellular Carcinoma. J Vasc Interv Radiol 26:1229-37
Qiu, Bo; Ackerman, Daniel; Sanchez, Danielle J et al. (2015) HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma. Cancer Discov 5:652-67
Ye, Jiangbin; Palm, Wilhelm; Peng, Min et al. (2015) GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2. Genes Dev 29:2331-6
Mucaj, V; Lee, S S; Skuli, N et al. (2015) MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma. Oncogene 34:2204-14

Showing the most recent 10 out of 93 publications