Honokiol confers immunogenicity by dictating calreticulin exposure, activating ER stress and inhibiting epithelial-to-mesenchymal transition
Journal
Molecular Oncology
Journal Volume
9
Journal Issue
4
Pages
834-849
Date Issued
2015
Author(s)
Abstract
Peritoneal dissemination is a major clinical obstacle in gastrointestinal cancer therapy, and it accounts for the majority of cancer-related mortality. Calreticulin (CRT) is over-expressed in gastric tumors and has been linked to poor prognosis. In this study, immunohistochemistry studies revealed that the up-regulation of CRT was associated with lymph node and distant metastasis in patients with gastric cancer specimens. CRT was significantly down-regulated in highly metastatic gastric cancer cell lines and metastatic animal by Honokiol-treated. Small RNA interference blocking CRT by siRNA-CRT was translocated to the cells in the early immunogenic response to Honokiol. Honokiol activated endoplasmic reticulum (ER) stress and down-regulated peroxisome proliferator-activated receptor-γ (PPARγ) activity resulting in PPARγ and CRT degradation through calpain-II activity, which could be reversed by siRNA-calpain-II. The Calpain-II/PPARγ/CRT axis and interaction evoked by Honokiol could be blocked by gene silencing or pharmacological agents. Both transforming growth factor (TGF)-β1 and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induced cell migration, invasion and reciprocal down-regulation of epithelial marker E-cadherin, which could be abrogated by siRNA-CRT. Moreover, Honokiol significantly suppressed MNNG-induced gastrointestinal tumor growth and over-expression of CRT in mice. Knockdown CRT in gastric cancer cells was found to effectively reduce growth ability and metastasis in vivo. The present study provides insight into the specific biological behavior of CRT in epithelial-to-mesenchymal transition (EMT) and metastasis. Taken together, our results suggest that the therapeutic inhibition of CRT by Honokiol suppresses both gastric tumor growth and peritoneal dissemination by dictating early translocation of CRT in immunogenic cell death, activating ER stress, and blocking EMT. ? 2015 Federation of European Biochemical Societies.
Subjects
Calreticulin; Carcinogenesis; Endoplasmic reticulum stress; Epithelial-to-mesenchymal transition; Immunogenic cell death
SDGs
Other Subjects
calpain 2; calpastatin; calreticulin; honokiol; methylnitronitrosoguanidine; peroxisome proliferator activated receptor gamma; small interfering RNA; transforming growth factor beta1; uvomorulin; biphenyl derivative; calpain; calreticulin; honokiol; lignan; peroxisome proliferator activated receptor gamma; protein binding; tumor marker; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; Article; cancer immunotherapy; cancer inhibition; cancer patient; cell invasion; cell migration; controlled study; distant metastasis; down regulation; drug efficacy; drug potentiation; endoplasmic reticulum stress; epithelial mesenchymal transition; female; gastric cancer cell line; gene overexpression; gene silencing; human; human cell; human tissue; immune response; immunogenicity; immunohistochemistry; lymph node metastasis; male; metastasis potential; mouse; nonhuman; peritoneum metastasis; priority journal; protein degradation; RNA interference; signal transduction; stomach cancer; tumor invasion; upregulation; adult; animal; Bagg albino mouse; C57BL mouse; cell death; drug effects; endoplasmic reticulum stress; epithelial mesenchymal transition; genetics; immunology; macrophage; metabolism; middle aged; pathology; phagocytosis; promoter region; stomach tumor; tumor cell line; Animalia; Mus; Adult; Animals; Biomarkers, Tumor; Biphenyl Compounds; Calpain; Calreticulin; Cell Death; Cell Line, Tumor; Down-Regulation; Endoplasmic Reticulum Stress; Epithelial-Mesenchymal Transition; Female; Gene Knockdown Techniques; Humans; Lignans; Macrophages; Male; Methylnitronitrosoguanidine; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Neoplasm Invasiveness; Phagocytosis; PPAR gamma; Promoter Regions, Genetic; Protein Binding; Stomach Neoplasms; Up-Regulation
Type
journal article