1. Academic Validation
  2. Accelerated degradation of cFLIPL and sensitization of the TRAIL DISC-mediated apoptotic cascade by pinoresinol, a lignan isolated from Rubia philippinensis

Accelerated degradation of cFLIPL and sensitization of the TRAIL DISC-mediated apoptotic cascade by pinoresinol, a lignan isolated from Rubia philippinensis

  • Sci Rep. 2019 Sep 18;9(1):13505. doi: 10.1038/s41598-019-49909-0.
So-Ra Lee 1 Khong Trong Quan 2 Hee Sun Byun 1 InWha Park 2 Kidong Kang 1 Xuezhe Piao 1 Eunjin Ju 1 Hyunju Ro 3 MinKyun Na 4 Gang Min Hur 5
Affiliations

Affiliations

  • 1 Department of Pharmacology and Department of Medical Science, College of Medicine, Chungnam National University, 266 Munhwa-ro, Daejeon, 35015, Republic of Korea.
  • 2 College of Pharmacy, Chungnam National University, Daejeon, 34134, Republic of Korea.
  • 3 Department of Biological Sciences, College of Biosciences and Biotechnology, Chungnam National University, Daejeon, 34134, Republic of Korea.
  • 4 College of Pharmacy, Chungnam National University, Daejeon, 34134, Republic of Korea. mkna@cnu.ac.kr.
  • 5 Department of Pharmacology and Department of Medical Science, College of Medicine, Chungnam National University, 266 Munhwa-ro, Daejeon, 35015, Republic of Korea. gmhur@cnu.ac.kr.
Abstract

Plant-derived Lignans have numerous biological effects including anti-tumor and anti-inflammatory activities. Screening of purified constituents of Rubia philippinensis from human glioblastoma cells resistant to TNF-related apoptosis-inducing ligand (TRAIL) has suggested that the lignan pinoresinol was a highly active TRAIL sensitizer. Here we show that treatment with nontoxic doses of pinoresinol in combination with TRAIL induced rapid Apoptosis and Caspase activation in many types of glioblastoma cells, but not in normal astrocytes. Analyses of apoptotic signaling events revealed that pinoresinol enhanced the formation of TRAIL-mediated death-inducing signaling complex (DISC) and complete processing of procaspase-8 within the DISC in glioblastoma cells, in which Caspase-8 was inactivated. Mechanistically, pinoresinol downregulated the expression of cellular FLICE-inhibitory protein (cFLIPL) and Survivin through proteasome-mediated degradation, without affecting death receptors or downstream intracellular apoptosis-related proteins. Furthermore, the sensitization of TRAIL-mediated Apoptosis by pinoresinol strictly depended on the expression level of cFLIPL, which was regulated through de novo protein synthesis, rather than by NF-κB or p53 signaling. Taken together, our results indicate that pinoresinol facilitates DISC-mediated Caspase-8 activation by targeting cFLIPL in an early event in apoptotic signaling, which provides a potential therapeutic module for TRAIL-based chemotherapy.

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