Exploring Mechanisms of Multi-Drug Resistance in Cancer Cells Mediated by CCTβ Overexpression
Date Issued
2014
Date
2014
Author(s)
Liao, Hsuan-Yun
Abstract
Among the mechanisms causing drug resistance, the β subunit of chaperonin containing t-complex 1 (CCT), a molecular chaperonin that facilitates protein folding in eukaryotic cytosol, has been found up-regulated in drug resistant cancer cell lines as well as MDR1. However, the mechanisms underlying CCTβ expression and MDR1 expression are not fully understood. In this thesis, first of all, we examined the other ABC transporters besides MDR1 and found the expression levels of three clinically studied MDR1, MRP1, and BCRP have been increased by overexpressing CCTβ and decreased by knockdown of CCTβ. Considering that the pumping efficiency is not proportional to the expression level for these ABC transporters, we further examined their functional levels. We found the functional levels of three ABC transporters were elevated in drug resistant cell lines as well as in CCTβ-overexpression cell lines but reduced in CCTβ-knockdown cell lines. Importantly, a post-translationally modified form of β-catenin in nucleus was found to be mediated by the expression level of CCTβ and regulate the expressions of ABC transporters. In addition, the expression of ABC transporters has been related to transcription activity of β-catenin [1-3]. These results indicate that CCTβ can regulate protein expression and function of ABC transporters via β-catenin.
Furthermore, apart from ABC transporters, increasing survival signaling and anti-apoptotic signaling cause increased survival rates and chemoresistance in cancer cells. First, anti-apoptotic protein Bcl2, which participates in preventing the release of cytochrome C from mitochondria, was shown to be overexpressed in drug resistant 7TR and CCT-β overexpressed MCF-7. Moreover, in this study, the interaction between XIAP and CCTβ was identified in 7TR, and XIAP overexprssion was identified in MCF7 overexpressing CCTβ cell line. On the other hand, knockdown of CCTβ decreased the expression of XIAP. However, caspase7 and cleaved caspase7 were found up-regulated in 7TR drug resistant cells and CCTβ-overexpressed MCF7 cells. These results indicate that CCTβ interacts and stabilizes XIAP from degradation, leading to the formation of XIAP: p12/p19-caspase7 complex to prevent cell death.
In summary, these studies explored the possible mechanisms of drug resistance originated from CCTβ overexpression, which include β-catenin-mediated expressional and functional up-regulation of ABC transporters, increase of anti-apoptotic Bcl2 to prevent cytochrome c-mediated apoptosis, and raise of XIAP to form complexes with caspase 7 to prevent apoptosis. These results enhance our understanding in drug resistance caused by multiple causes. The proteins involved in the drug resistance or those interacting with CCTβ could be valuable targets for cancer drug design.
Subjects
多重抗藥性
藥物運輸蛋白
SDGs
Type
thesis
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