Chaperonin-Containing TCP-1 Promotes Cancer Chemoresistance and Metastasis through the AKT-GSK3β-β-Catenin and XIAP-Survivin Pathways

SIMPLE SUMMARY: CCT is a chaperonin that participates in folding intracellular proteins. We found that endogenously high expression of the subunit CCT-β is associated with a poorer chemotherapy response in clinical cancer patients. Using two cancer cell lines with higher CCT-β levels, a triple-negative breast cancer cell line MDA-MB-231 and a highly metastatic non-small-cell lung cancer cell line CL1-5, we demonstrated that upregulation of CCT-β expression correlated with chemoresistance and metastasis of these cancer cells in vitro and in vivo. Mechanistic studies allowed us to identify the AKT-GSK3β-β-catenin and XIAP-Survivin pathways promoted by CCT-β to account for the observations. The results provided by our studies are important for developing diagnostic and therapeutic strategies for combating CCT-β-overexpressed cancers. ABSTRACT: Chaperonin-containing TCP-1 (CCT) is a chaperonin composed of eight subunits that participates in intracellular protein folding. Here, we showed that increased levels of subunits of CCT, particularly CCT-β, were significantly correlated with lower survival rates for cancer patients. Endogenously high expression of CCT-β was found in cancer cell lines, such as the triple-negative breast cancer cell line MDA-MB-231 and the highly metastatic non-small-cell lung cancer cell line CL1-5. Knocking down CCT-β in these cancer cells led to decreased levels of anti-apoptotic proteins, such as XIAP, as well as inhibited phosphorylation of Ser473-AKT and GSK3, resulting in decrease of the nucleus-entering form of β-catenin; these changes reduced the chemoresistance and migration/invasion of the cells. Conversely, overexpression of CCT-β recovered the chemoresistance and cell migration/invasion by promoting the AKT-GSK3β-β-catenin and XIAP-Survivin pathways. Coimmunoprecipitation data revealed that the CCT complex might directly bind and stabilize XIAP and β-catenin. This study not only elucidates the roles of CCT in chemoresistance and metastasis, which are two major obstacles for current cancer therapy, but also provides a possible therapeutic strategy against cancers with overexpressed CCT-β.