Fas is a member of the death receptor superfamily. The major and best known function of Fas is apoptosis. Germline and somatic mutations or deletions of FAS or FASL gene coding sequences in humans lead to autoimmune lymphoproliferative syndrome. Patients with autoimmune lymphoproliferative syndrome exhibit increased risk of both hematopoietic and non-hematopoietic cancers. Furthermore, FAS and FASL gene promoter polymorphisms are associated with decreased Fas expression level and increased risk of both hematopoietic and non-hematopoietic cancer developments in humans. Stimulation of Fas receptor also activates """"""""non-apoptotic"""""""" signaling, notably NF-?B activation. However, the function of Fas-mediated NF-?B activation remains largely unknown. Our preliminary studies demonstrated that canonical NF-?B is a transcription activator of Fas and a promoter of Fas-mediated apoptosis, whereas the alternate NF-?B is a transcription repressor of Fas and suppressor of Fas-mediated apoptosis in both human colon carcinoma cells and in mouse embryonic fibroblasts. Furthermore, our preliminary studies demonstrated that blocking the canonical NF-?B activation results in a significantly increase of colon carcinoma cell metastatic potential in vivo. Based on these observations, we hypothesize that subunit composition is the molecular switch that controls the contrasting functions of the NF-?B protein complexes in Fas-mediated apoptosis and pharmacological intervention of Fas resistance is an effective approach to increase CTL immunotherapy efficacy against colon cancer metastasis. Our long-term goal is to develop a Fas-based therapy to suppress human colorectal cancer metastasis. We propose to carry out three specific aims in this project: 1) test the hypothesis that subunit composition of the NF-?B protein complex determines NF-?B functions in colon carcinoma cell apoptosis and survival;2) test the hypothesis that NF-?B regulates Fas-mediated apoptosis pathways to mediate colon carcinoma development in vivo;and 3) test the hypothesis that apoptosis sensitization chemotherapy increases the efficacy of immunotherapy against colon carcinoma metastasis. This research project has the potential to develop an adjunct therapy to overcome Fas resistance to increase the efficacy of immunotherapy for effective suppression of spontaneous colon cancer metastasis.

Public Health Relevance

This research project has the potential to develop an adjunct therapy to overcome Fas resistance to increase the efficacy of immunotherapy for effective suppression of spontaneous colon cancer metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA182518-01A1
Application #
8761837
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Welch, Anthony R
Project Start
2014-08-01
Project End
2019-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Coe, Genevieve L; Redd, Priscilla S; Paschall, Amy V et al. (2016) Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes. Sci Rep 6:30816
Simon, Priscilla S; Bardhan, Kankana; Chen, May R et al. (2016) NF-κB functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression. Oncotarget 7:23395-415
Paschall, Amy V; Yang, Dafeng; Lu, Chunwan et al. (2015) H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance. J Immunol 195:1868-82
Paschall, Amy V; Liu, Kebin (2015) Epigenetic Regulation of Apoptosis and Cell Cycle Regulatory Genes in Human Colon Carcinoma Cells. Genom Data 5:189-191
Bardhan, Kankana; Paschall, Amy V; Yang, Dafeng et al. (2015) IFNγ Induces DNA Methylation-Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer. Cancer Immunol Res 3:795-805
Simon, Priscilla S; Sharman, Sarah K; Lu, Chunwan et al. (2015) The NF-κB p65 and p50 homodimer cooperate with IRF8 to activate iNOS transcription. BMC Cancer 15:770
Paschall, Amy V; Zhang, Ruihua; Qi, Chen-Feng et al. (2015) IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. J Immunol 194:2369-79