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Codium fragile F2 sensitize colorectal cancer cells to TRAIL-induced apoptosis via c-FLIP ubiquitination

Park, Seong Hye, Kim, Jung Lim, Jeong, Soyeon, Kim, Bo Ram, Na, Yoo Jin, Jo, Min Jee, Yun, Hye Kyeong, Jeong, Yoon A, Kim, Dae Yeong, Kim, Bu Gyeom, You, SangGuan, Oh, Sang Cheul, Lee, Dae-Hee
Biochemical and biophysical research communications 2019 v.508 no.1 pp. 1-8
Codium fragile, apoptosis, caspase-8, colorectal neoplasms, death domain receptors, drug therapy, flavonoids, fruits, ligands, necrosis, neoplasm cells, pro-apoptotic proteins, protein content, proteolysis, ubiquitination, vegetables
This study demonstrates that combined treatment with subtoxic doses of Codium extracts (CE), a flavonoid found in many fruits and vegetables, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), induces apoptosis in TRAIL-resistant colorectal cancer (CRC) cells. Effective induction of apoptosis by combined treatment with CE and TRAIL was not blocked by Bcl-xL overexpression, which is known to confer resistance to various chemotherapeutic agents. While TRAIL-mediated proteolytic processing of procaspase-3 was partially blocked in various CRC cells treated with TRAIL alone, co-treatment with CE efficiently recovered TRAIL-induced caspase activation. We observed that CE treatment of CRC cells did not change the expression of anti-apoptotic proteins and pro-apoptotic proteins, including death receptors (DR4 and DR5). However, CE treatment markedly reduced the protein level of the short form of the cellular FLICE-inhibitory protein (c-FLIPS), an inhibitor of caspase-8, via proteasome-mediated degradation. Collectively, these observations show that CE recovers TRAIL sensitivity in various CRC cells via down-regulation of c-FLIPS.