Abstract
Treatments for aggressive cancers like triple negative breast cancer (TNBC) and small-cell lung cancer (SCLC) have not improved and remain associated with debilitating side effects. There is an unmet medical need for better, druggable targets and improved therapeutics. To this end, we investigated the role of Chaperonin-Containing TCP1 (CCT), an evolutionarily conserved protein-folding complex composed of eight subunits (CCT1-8), in oncogenesis. Our laboratory was the first to report that the CCT2 subunit is highly expressed in breast cancer and could be therapeutically targeted. To determine whether CCT is a marker of disease progression in other cancers, we analyzed CCT2 gene expression in liver, prostate and lung cancer, using publicly available genetic databases, and confirmed findings by assessing CCT2 and client proteins, like STAT3, in tumor tissues by immunohistochemistry. We found that CCT2 was high in all cancers, especially SCLC, and correlated with decreased patient survival. We tested CT20p, the peptide therapeutic developed by our laboratory to inhibit CCT, on SCLC and primary lung cells, finding that CT20p was only cytotoxic to SCLC cells. Since SCLC currently lacks targeted therapeutics, our work yielded a new targeted agent that could improve lung cancer mortality. To establish a mechanism of action for CT20p, we partially knocked out CCT2 in TNBC cells, which decreased tumorigenicity in mice and reduced levels of essential proteins like STAT3. To confirm, we overexpressed CCT2 in non-tumorigenic cells and conferred tumor-like characteristics such as increased migration and elevated STAT3. These studies positioned us to develop and validate a strategy for discovery of new small molecule inhibitors of CCT. We thus advanced the field of cancer research by demonstrating that CCT could have diagnostic potential for cancers, such as SCLC and TNBC, that are a significant cause of human death and showed that targeting CCT is a promising therapeutic approach.
Notes
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Graduation Date
2017
Semester
Fall
Advisor
Khaled, Annette
Degree
Doctor of Philosophy (Ph.D.)
College
College of Medicine
Department
Burnett School of Biomedical Sciences
Degree Program
Biomedical Sciences
Format
application/pdf
Identifier
CFE0007280
URL
http://purl.fcla.edu/fcla/etd/CFE0007280
Language
English
Release Date
June 2019
Length of Campus-only Access
1 year
Access Status
Doctoral Dissertation (Open Access)
STARS Citation
Carr, Ana, "Chaperonin Containing TCP1 (CCT) as a Target for Cancer Therapy" (2017). Electronic Theses and Dissertations. 6032.
https://stars.library.ucf.edu/etd/6032