伴侶蛋白TCP-1透過AKT-GSK3β-β-Catenin和XIAP-Survivin途徑促進癌症的化學抗性和轉移

Abstract

Chaperonin-containing TCP-1（CCT）是由八個亞基組成的伴侶蛋白，參與細胞內蛋白質折疊。在這裡，我們表明了CCT八個亞基水平的升高與癌症患者低生存率有顯著相關性，尤其是CCT-β 的過度表現造成癌症患者較低生存率。在三陰性乳腺癌細胞株MDA-MB-231和非小細胞肺癌細胞株CL1-5這兩個具有高度轉移特性的細胞株中可以發現CCT-β過度表現。而降低這些癌細胞中的CCT-β會導致抗凋亡蛋白（例如XIAP）水平降低，以及抑制Ser473-AKT和GSK3的磷酸化，進而導致β-catenin入核減少。這些改變降低了細胞的化學抗性和遷移/侵襲能力。反之，CCT-β的過表達透過促進AKT-GSK3β-β-catenin和XIAP-Survivin途徑恢復了化學抗性和細胞遷移/侵襲能力。免疫共沉澱數據表明，CCT複合物可能直接結合並穩定XIAP和β-catenin。這項研究不僅闡明了CCT在化學抗性和轉移中的作用，也是當前癌症治療的兩個主要障礙，更能為CCT-β過表達的癌症提供了可能的治療策略。

Chaperonin containing t-complex 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.