You are here

Chaperonin Containing TCP1 (CCT) as a Target for Cancer Therapy

Download pdf | Full Screen View

Date Issued:
2017
Abstract/Description:
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.
Title: Chaperonin Containing TCP1 (CCT) as a Target for Cancer Therapy.
16 views
6 downloads
Name(s): Carr, Ana, Author
Khaled, Annette, Committee Chair
Altomare, Deborah, Committee Member
Tigno-Aranjuez, Justine, Committee Member
Fernandez-Valle, Cristina, Committee Member
University of Central Florida, Degree Grantor
Type of Resource: text
Date Issued: 2017
Publisher: University of Central Florida
Language(s): English
Abstract/Description: 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.
Identifier: CFE0007280 (IID), ucf:52191 (fedora)
Note(s): 2017-12-01
Ph.D.
Medicine, Burnett School of Biomedical Sciences
Doctoral
This record was generated from author submitted information.
Subject(s): Targeted cancer therapy -- chaperonin containing TCP1 -- CT20p -- small-cell lung cancer -- triple-negative breast cancer
Persistent Link to This Record: http://purl.flvc.org/ucf/fd/CFE0007280
Restrictions on Access: campus 2019-06-15
Host Institution: UCF

In Collections