Maritoclax Enhances TRAIL-Induced Apoptosis via CHOP-Mediated Upregulation of DR5 and miR-708-Mediated Downregulation of cFLIP.
Mi-Yeon JeonKyoung-Jin MinSeon Min WooSeung Un SeoYoung Hyun ChoiSang Hyun KimDong Eun KimTae-Jin LeeShin KimJong-Wook ParkTaeg-Kyu KwonPublished in: Molecules (Basel, Switzerland) (2018)
Maritoclax, an active constituent isolated from marine bacteria, has been known to induce Mcl-1 downregulation through proteasomal degradation. In this study, we investigated the sensitizing effect of maritoclax on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human renal carcinoma cells. We found that combined treatment with maritoclax and TRAIL markedly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung cancer (A549) and hepatocellular carcinoma (SK-Hep1) cells. The upregulation of death receptor 5 (DR5) and downregulation of cellular FLICE-inhibitory protein (cFLIP) were involved in maritoclax plus TRAIL-induced apoptosis. Maritoclax-induced DR5 upregulation was regulated by induction of C/EBP homologous protein (CHOP) expression. Interestingly, maritoclax induced cFLIP downregulation through the increased expression of miR-708. Ectopic expression of cFLIP prevented combined maritoclax and TRAIL-induced apoptosis. Taken together, maritoclax sensitized TRAIL-induced apoptosis through CHOP-mediated DR5 upregulation and miR-708-mediated cFLIP downregulation.
Keyphrases
- induced apoptosis
- signaling pathway
- cell proliferation
- poor prognosis
- endoplasmic reticulum stress
- long non coding rna
- oxidative stress
- pi k akt
- diabetic rats
- binding protein
- diffuse large b cell lymphoma
- editorial comment
- cell cycle arrest
- high glucose
- long noncoding rna
- endothelial cells
- protein protein
- dna repair
- small molecule
- cell death
- amino acid
- atomic force microscopy