Defects in apoptosis regulation are thought to be a prerequisite for cancer development however the nature of the apoptotic pathways that are defective is poorly understood. The identification and understanding of apoptotic pathways that are selectively disrupted during cancer development may provide new insights into cancer development and identify novel therapeutic targets. We are studying a novel apoptosis pathway that is induced by the death domain of the adaptor protein FADD (FADD-DD). This pathway has unusual characteristics that suggest it is an example of an apoptosis pathway that has to be disrupted for breast or prostate cancer to develop. Our previous studies show that FADD-DD can induce apoptosis only in normal epithelial cells. This cell type-specific response works via a previously unrecognized mechanism that is separate from the established mode of action of FADD and may involve a novel FADD-binding protein called PL31. The novel pathway is specifically disrupted when epithelial cells become immortalized. However, this disruption is unrelated to inactivation of the known pathways (p53, Rb & telomerase) that are involved in immortalization. An oncogene (SV40 T antigen) can confer resistance to this apoptosis pathway in normal cells without affecting other apoptosis mechanisms, while a specific tumor suppressor (Bin1) can confer sensitivity to this pathway in cancer cells. Endogenous FADD protein can activate this pathway when it is stimulated by TRAIL. Thus, we have identified a new apoptosis pathway that is activated by TRAIL, involves FADD, may involve PL31 and Bin1 and is specifically disrupted by SV40 T antigen through a p53- and Rb independent mechanism that is associated with cell immortalization. This data will lead us to develop our hypothesis: FADD participates in a novel apoptotic pathway that is specifically disrupted during breast or prostate cancer development. Here, we test this hypothesis and determine the roles of PL31, Bin1, T antigen and TRAIL with the following aims: 1) Determine how FADD-DD induces apoptosis of normal epithelial cells. 2). Determine why immortal cells are resistant to FADD-DD-induced apoptosis. 3). Characterize the physiologic signal that activates the FADD-DD-dependent pathway in normal epithelial cells. These studies should provide a detailed understanding of a previously unrecognized apoptosis pathway that may be intimately involved in cancer development.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA111421-02
Application #
7021465
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Spalholz, Barbara A
Project Start
2005-02-22
Project End
2010-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
2
Fiscal Year
2006
Total Cost
$297,002
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Maycotte, Paola; Jones, Kenneth L; Goodall, Megan L et al. (2015) Autophagy Supports Breast Cancer Stem Cell Maintenance by Regulating IL6 Secretion. Mol Cancer Res 13:651-8
Yonekawa, Tohru; Gamez, Graciela; Kim, Jihye et al. (2015) RIP1 negatively regulates basal autophagic flux through TFEB to control sensitivity to apoptosis. EMBO Rep 16:700-8
Gump, Jacob M; Thorburn, Andrew (2014) Sorting cells for basal and induced autophagic flux by quantitative ratiometric flow cytometry. Autophagy 10:1327-34
Levy, Jean M Mulcahy; Thompson, Joshua C; Griesinger, Andrea M et al. (2014) Autophagy inhibition improves chemosensitivity in BRAF(V600E) brain tumors. Cancer Discov 4:773-80
Thorburn, Andrew (2014) Autophagy and its effects: making sense of double-edged swords. PLoS Biol 12:e1001967
Thorburn, Jacqueline; Andrysik, Zdenek; Staskiewicz, Leah et al. (2014) Autophagy controls the kinetics and extent of mitochondrial apoptosis by regulating PUMA levels. Cell Rep 7:45-52
Gump, Jacob M; Staskiewicz, Leah; Morgan, Michael J et al. (2014) Autophagy variation within a cell population determines cell fate through selective degradation of Fap-1. Nat Cell Biol 16:47-54
Morgan, Michael J; Gamez, Graciela; Menke, Christina et al. (2014) Regulation of autophagy and chloroquine sensitivity by oncogenic RAS in vitro is context-dependent. Autophagy 10:1814-26
Goodall, Megan; Thorburn, Andrew (2014) Identifying specific receptors for cargo-mediated autophagy. Cell Res 24:783-4
Thorburn, Andrew; Thamm, Douglas H; Gustafson, Daniel L (2014) Autophagy and cancer therapy. Mol Pharmacol 85:830-8

Showing the most recent 10 out of 33 publications