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

Yan Jin Liu, Vathan Kumar, Yuan Feng Lin, Po Huang Liang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

We have previously demonstrated the ability of I-Trp to disrupt the protein-protein interaction of β-tubulin with chaperonin-containing TCP-1β (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-μM EC"5"0, 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.

Original languageEnglish
Article numbere3052
JournalCell Death and Disease
Volume8
Issue number9
DOIs
Publication statusPublished - Sep 14 2017
Externally publishedYes

Fingerprint

Chaperonin Containing TCP-1
Tubulin
Cell Line
Neoplasms
Proteolysis
Triple Negative Breast Neoplasms
Ubiquitination
Stomach Neoplasms
Colorectal Neoplasms
Proteins
Apoptosis

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Disrupting CCT-β : β-tubulin selectively kills CCT-βoverexpressed cancer cells through MAPKs activation. / Liu, Yan Jin; Kumar, Vathan; Lin, Yuan Feng; Liang, Po Huang.

In: Cell Death and Disease, Vol. 8, No. 9, e3052, 14.09.2017.

Research output: Contribution to journalArticle

@article{e36e076847b3468f8889463dbb71ebcd,
title = "Disrupting CCT-β: β-tubulin selectively kills CCT-βoverexpressed cancer cells through MAPKs activation",
abstract = "We have previously demonstrated the ability of I-Trp to disrupt the protein-protein interaction of β-tubulin with chaperonin-containing TCP-1β (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-μM EC{"}5{"}0, 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.",
author = "Liu, {Yan Jin} and Vathan Kumar and Lin, {Yuan Feng} and Liang, {Po Huang}",
year = "2017",
month = "9",
day = "14",
doi = "10.1038/cddis.2017.425",
language = "English",
volume = "8",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "9",

}

TY - JOUR

T1 - Disrupting CCT-β

T2 - β-tubulin selectively kills CCT-βoverexpressed cancer cells through MAPKs activation

AU - Liu, Yan Jin

AU - Kumar, Vathan

AU - Lin, Yuan Feng

AU - Liang, Po Huang

PY - 2017/9/14

Y1 - 2017/9/14

N2 - We have previously demonstrated the ability of I-Trp to disrupt the protein-protein interaction of β-tubulin with chaperonin-containing TCP-1β (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-μM EC"5"0, 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.

AB - We have previously demonstrated the ability of I-Trp to disrupt the protein-protein interaction of β-tubulin with chaperonin-containing TCP-1β (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-μM EC"5"0, 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.

UR - http://www.scopus.com/inward/record.url?scp=85029506345&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029506345&partnerID=8YFLogxK

U2 - 10.1038/cddis.2017.425

DO - 10.1038/cddis.2017.425

M3 - Article

AN - SCOPUS:85029506345

VL - 8

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 9

M1 - e3052

ER -