Codium fragile F2 sensitize colorectal cancer cells to TRAIL-induced apoptosis via c-FLIP ubiquitination |
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Authors: | Seong Hye Park Jung Lim Kim Soyeon Jeong Bo Ram Kim Yoo Jin Na Min Jee Jo Hye Kyeong Yun Yoon A Jeong Dae Yeong Kim Bu Gyeom Kim SangGuan You Sang Cheul Oh Dae-Hee Lee |
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Affiliation: | 1. Graduate School of Medicine, Korea University College of Medicine, Seoul, 152-703, Republic of Korea;2. Department of Oncology, Korea University Guro Hospital, Seoul, 152-703, Republic of Korea;3. Department of Marine Food Science and Technology, Gangneung-Wonju National University, Gangwon 210-702, Republic of Korea |
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Abstract: | 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. |
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Keywords: | Codium extracts (CE) TRAIL c-FLIP Ubiquitination TRAIL TNF-Related apoptosis-inducing ligand TNF Tumor necrosis factor FLIP FLICE-Like inhibitory protein FITC Fluorescein isothiocyanate PARP Poly (ADP-Ribose) polymerase PBS Phosphate-buffered saline PI Propidium iodide CHX Cycloheximide SDS-PAGE Sodium dodecyl sulfate-polyacrylamide gel electrophoresis |
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