Disrupting CCT-β?:?β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation

摘要

We have previously demonstrated the ability of I-Trp to disrupt the protein–protein interaction of β -tubulin with chaperonin-containing TCP-1 β (CCT- β ). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT- β overexpression. In this study, we screened a panel of cancer cell lines, finding CCT- β overexpression in the triple-negative breast cancer cell line MDA-MB-231, colorectal cancer cell lines Colo205 and HCT116, and a gastric cancer cell line MKN-45. Thus, I-Trp killed these cancers with sub- to low- μ M EC 50 , whereas it was non-toxic to MCF-10A. We then synthesized analogs of I-Trp and evaluated their cytotoxicity. Furthermore, apoptotic mechanism investigations revealed the activation of both protein ubiquitination/degradation and ER-associated protein degradation pathways. These pathways proceeded through activation of MAPKs at the onset of CCT- β : β -tubulin complex disruption. We thus establish an effective strategy to treat CCT- β overexpressed cancers by disrupting the CCT- β : β -tubulin complex.