Synergistic apoptosis following endoplasmic reticulum stress aggravation in mucinous colon cancer.
Orphanet J Rare Dis
; 15(1): 211, 2020 08 18.
Article
em En
| MEDLINE
| ID: mdl-32811515
ABSTRACT
BACKGROUND:
Mucinous colon cancers (MCC) are characterized by abundant production of mucin 2 (MUC2) protein and are less sensitive to standard systemic chemotherapy. We postulated that severe/persistent endoplasmic reticulum stress (ERS) aggravation in MCC would overwhelm compensatory cytoprotective pathways and induce apoptosis.RESULTS:
Basal levels of ERS markers were higher in MCC and dnTCF-LS174T cells than non-mucinous tumors and these levels were significantly increased by combinatorial treatment with ERS aggravators celecoxib + orlistat. Combination treatment inhibited cell viability and synergistically induced apoptosis. Treatment-induced cell death was ERS-dependent, apoptotic pathways were not activated following knockdown of ERS protein CHOP. Dual drug treatment significantly reduced mucinous tumor growth in vivo and induced ERS and apoptosis, consistent with in vitro experiments.CONCLUSIONS:
Novel therapies are needed since MCC are more resistant to standard systemic chemotherapy. This study suggests ERS aggravation is a viable therapeutic strategy to reduce tumor growth in MCC.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias do Colo
/
Estresse do Retículo Endoplasmático
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article