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Cited by 88Cell death mechanisms and regulationTraditional Chinese Medicine AnalysisNatural Compounds in Disease Treatment

Simultaneous induction of apoptosis and necroptosis by Tanshinone IIA in human hepatocellular carcinoma HepG2 cells

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Lin, C-Y, Chang, T-W, Hsieh, W-H, Hung, M-C, Lin, I-H, Lai, S-C, Tzeng, Y-J·2016·Cell Death Discovery
DOI 10.1038/cddiscovery.2016.65PMC PMC5045965
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Abstract

Tanshinone IIA (Tan IIA), a constituent of the traditional medicinal plant Salvia miltiorrhiza BUNGE, has been reported to possess anticancer activity through induction of apoptosis in many cancer cells. Surprisingly, the present study finds that Tan IIA simultaneously causes apoptosis and necroptosis in human hepatocellular carcinoma HepG2 cells. We further find that apoptosis can be converted to necroptosis by pan-caspase inhibitor Z-VAD-fmk, and the two death modes can be blocked by necroptotic inhibitor necrostatin-1. The underlying mechanisms are revealed by analysis of the signaling molecules using western blotting. In control cells, FLICE inhibitory protein in short form (FLIP S) is expressed in relatively high levels and binds to caspase 8 in ripoptosome, which supposedly sustains cell survival. However, in Tan IIA-treated cells, FLIP S is down-regulated and may thus cause homodimer formation of cleaved caspase 8, cleavage of receptor-interacting serine/threonine-protein kinases 1, 3 (RIP1, RIP3), and mixed-lineage kinase domain-like (MLKL), in turn leads to cell apoptosis. In parallel, Tan IIA causes necroptosis by forming a suggested necrosomal complex composed of RIP1/RIP3. Regarding the inhibitors, z-VAD-fmk diminishes the cleaved caspase 8, RIP1, RIP3, and MLKL induced by Tan IIA, and reconstructs the ripoptosome complex, which marks cells moving from apoptosis to necroptosis. Nec-1 recovers the Tan IIA down-regulated FLIP S, consequently causes FLIP S to form heterodimer with caspase 8 and thus block apoptosis. Meanwhile, cleaved forms of RIP1 and RIP3 were observed preventing necroptosis. Intriguingly, the cytotoxicity of tumor necrosis factor-related apoptosis-inducing ligand to HepG2 cells is enhanced by Tan IIA in a pilot study, which may be attributed to low FLIP S levels induced by Tan IIA. In short, Tan IIA simultaneously induces both Nec-1 inhibition and FLIP S regulation-mediated apoptosis/necroptosis, which has not been previously documented. Moreover, the involvement of the cleavage type of MLKL in executing necroptosis warrants further investigation.

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  • Tanshinone IIA might induce necroptosis in human hepatocellular carcinoma by promoting formation of a necrosomal complex composed of RIP1/RIP3.

    “Interestingly, Lin et al. demonstrated that Tanshinone IIA might also induce necroptosis in human HCC by promoting the formation of a necrosomal complex composed of receptor-interacting protein 1 (RIP1)/RIP3.96”

    From Drug repurposing for cancer therapy (2024) · cites this paper as [96]

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Authors
Lin, C.-Y., Chang, T.-W., Hsieh, W.-H., Hung, M.-C., Lin, I.-H., Lai, S.-C., & Tzeng, Y.-J.
Affiliations
  • Tzu Chi University (TW)
  • Hualien District Agricultural Research and Extension Station Council of Agriculture (TW)
Corresponding author
Tzeng, Y-J
Venue
Cell Death Discovery
Publisher
Springer Science and Business Media LLC
Published
2016-10-03
Volume
2
Issue
1
Pages
16065-16065
ISSN
2058-7716 (ISSN-L)
DOI
10.1038/cddiscovery.2016.65
PMC
PMC5045965
OpenAlex
W2528762358
Cited by
88
References
1
Citations by year
2026: 4 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 9 · 2021: 12 · 2020: 12 · 2019: 18 · 2018: 9 · 2017: 5
FWCI
5.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death Discovery (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Tzu Chi University
  • Deutscher Akademischer Austauschdienst
  • Ministry of Science and Technology, Taiwan (MOST103-2633-B320-001)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Complementary and alternative medicine › Traditional Chinese Medicine Analysis
  • Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
Keywords
tanshinone IIA, apoptosis, necroptosis, hepatocellular carcinoma, HepG2 cells, Salvia miltiorrhiza, c-FLIP, caspase-8, RIPK1, RIPK3, MLKL, necrostatin-1, z-VAD-fmk, TRAIL sensitization, death receptor signaling

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