Journal
BIOCHEMICAL PHARMACOLOGY
Volume 158, Issue -, Pages 243-260Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2018.10.019
Keywords
C-27-carboxylated oleanolic acids (C27OAs); TRAIL resistance; Death receptor; Caspase-8; DISC-mediated apoptosis
Categories
Funding
- National Research Foundation of Korea (NRF) - Korea government (MSIP) [2017R1A2A1A05001225, 2017R1A5A2015385, 2017R1A2A2A05001340]
- National Research Foundation of Korea [2017R1A2A2A05001340, 2017R1A2A1A05001225, 2017R1A5A2015385] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Despite recent tremendous progress, targeting of TNF-related apoptosis-inducing ligand (TRAIL) as a cancer therapy has limited success in many clinical trials, in part due to inactivation of death inducing signaling complex (DISC)-mediated caspase-8 signaling cascade in highly malignant tumors such as glioblastoma. In this study, screening of constituents derived from Astilbe rivularis for TRAIL-sensitizing activity identified C-27-carboxylated oleanolic acid derivatives (C27OAs) including 3 beta-hydroxyolean-12-en-27-oic acid (C27OA-1), 3 beta,6 beta,7 alpha-trihydroxyolean-12-en-27-oic acid (C27OA-2), and 3 beta-trans-p-coumaroyloxy-olean-12-en-27-oic acid (C27OA-3) as novel TRAIL sensitizers. Interestingly, these C27OAs did not affect apoptotic cell death induced by either ligation of other death receptor (DR) types, such as TNF and Fas or DNA damaging agents, which suggests that C27OAs effectively and selectively sensitize TRAIL -mediated caspase-8 activation. Mechanistically, C27OAs upregulate the expression of cell surface DR5 and DISC formation without affecting downstream intracellular apoptosis-related proteins. The upregulation of DR5 expression by C27OAs strictly depends on transactivation of C/EBP homology protein, which is regulated through the p38 MAPK pathway, rather than p53 and intracellular reactive oxygen species status. Taken together, our results identify the novel C27OAs as TRAIL sensitizers targeting the upstream DISC assembly of DR5, and provide a rationale for further development of C27OAs for facilitating TRAIL-based chemotherapy in glioblastoma patients.
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