Sea Cucumber (Stichopus japonicas) F2 Enhanced TRAIL-Induced Apoptosis via XIAP Ubiquitination and ER Stress in Colorectal Cancer Cells

Abstract

Natural products have shown great promise in sensitizing cells to TNF-related apoptosis-inducing ligand (TRAIL) therapy. Sea cucumber (SC) extracts possess antitumor activity, and hence their potential to sensitize colorectal cancer (CRC) cells to TRAIL therapy was evaluated. This study used Western blotting to evaluate the combination effects of SC and TRAIL in CRC, and determined the molecular mechanism underlying these effects. SC fractions and TRAIL alone did not affect apoptosis; however, combined treatment dramatically induced the apoptosis of CRC cells, but not of normal colon cells. Combined treatment induced the expression of apoptotic proteins (poly (ADP-ribose) polymerase (PARP), caspase 3, and 8), and this effect was markedly inhibited by the ubiquitination of X-linked inhibitor of apoptosis protein (XIAP). SC did not affect the mRNA levels, but it increased proteasomal degradation and ubiquitination of the XIAP protein. Furthermore, SC induced reactive oxygen species (ROS) production, thereby activating c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER) stress-related apoptotic pathways in CRC. Altogether, our results demonstrate that the SC F2 fraction may sensitize CRC cells to TRAIL-induced apoptosis through XIAP ubiquitination and ER stress.

<p>Inhibition of cyclinB1 Suppressed the Proliferation, Invasion, and Epithelial Mesenchymal Transition of Hepatocellular Carcinoma Cells and Enhanced the Sensitivity to TRAIL-Induced Apoptosis</p>

“…20 A variety of chemotherapeutic agents can block the cell cycle of tumor cells and enhance their sensitivity to TRAIL-induced apoptosis. [21][22][23] Since knockdown of cyclinB1 induced cell cycle arrest, we sought to determine whether it would contribute to TRAIL-induced apoptosis in HCC. Our study certified that knockdown of cyclinB1 sensitized HCC cells to TRAIL-induced apoptosis.…”

Role of phloretin as a sensitizer to TRAIL‑induced apoptosis in colon cancer

“…A previous study suggested that the inhibitory mechanisms of TRAIL in colon cancer included promotion of apoptosis and lymphocyte infiltration, as well as the inhibition of invasion and migration (14). To identify a successful cancer treatment method using TRAIL-R agonists, a variety of chemical compounds or natural products have been evaluated for their efficacies and mechanisms in sensitizing cancer cells to TRAIL-induced apoptosis (18)(19)(20). Kim et al (18) reported that sea cucumber enhanced TRAIL-mediated apoptosis by increasing proteasomal degradation of X-linked inhibitor of apoptosis protein (XIAP) and activating endoplasmic reticulum stress in CRC.…”

“…To identify a successful cancer treatment method using TRAIL-R agonists, a variety of chemical compounds or natural products have been evaluated for their efficacies and mechanisms in sensitizing cancer cells to TRAIL-induced apoptosis (18)(19)(20). Kim et al (18) reported that sea cucumber enhanced TRAIL-mediated apoptosis by increasing proteasomal degradation of X-linked inhibitor of apoptosis protein (XIAP) and activating endoplasmic reticulum stress in CRC. Another study reported that icariin, a chemical compound classified as a prenylated flavonol glycoside, sensitized colon cancer cells to TRAIL-induced apoptosis through reactive oxygen species-, ERK-and CCAAT enhancer-binding protein homologous protein-mediated modulation of death receptor (DR)-4 and -5 expression (19).…”

“…Despite efforts to clarify the inhibitory mechanism of phloretin in colon cancer, to the best of our knowledge, the association between phloretin and TRAIL-induced apoptosis has not been reported yet. Given that one anticancer mechanism of phloretin in CRC is the induction of apoptosis ( 17 , 18 ), the present study investigated possible synergistic effects of phloretin on TRAIL-induced apoptosis in CRC. The present study provided information on the mechanism by which phloretin exerts inhibitory effects on CRC using human colon cancer cell lines.…”

Sea cucumber Cucumaria frondosa fucoidan inhibits osteosarcoma adhesion and migration by regulating cytoskeleton remodeling

“…Sea cucumber is a widely used traditional Chinese medicine (TCM) with numerous healthy benefits (13). It is rich in a variety of bioactive components, such as polysaccharide, polypeptide and saponins (13)(14)(15)(16). Sea cucumber fucoidan has been reported to have anticoagulant, anti-hyperglycemic, anti-inflammatory, and immunomodulatory activity (17)(18)(19).…”