Chlorophyllin Inhibits Mammalian Thioredoxin Reductase 1 and Triggers Cancer Cell Death

Food colorants are widely used by humans in food production and preparation; however, their potential toxicity requires an in-depth analysis. In this study, five out of 15 commercial food colorants, namely, lutein, betanin, caramel, crocin and chlorophyll, significantly inhibited wild type selenoprotein thioredoxin reductase 1 (TrxR1, TXNRD1) in vitro. The hyperactive Sec498 residue of TrxR1 was targeted by those five colorants, which was confirmed by the site-directed mutagenesis of TrxR1. Furthermore, two colorants, chlorophyll and betanin, triggered the oligomerization of TrxR1. A chlorophyll-derived compound, chlorophyllin, irreversibly inhibited the 5,5′-dithiobis-2-nitrobenzoic acid (DTNB) reducing activity of TrxR1 with Kinact = 6.96 × 10−3 ± 0.49 × 10−3 µM−1 min−1. Moreover, chlorophyllin reduced the cellular TrxR activity, leading to reactive oxygen species (ROS) accumulation and, subsequently, promoting cancer cell death. In conclusion, this study might contribute to understand the food safety of commercial colorants and provide chemotherapeutic compounds by targeting TrxR1.

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Thiol antioxidants sensitize malabaricone C induced cancer cell death via reprogramming redox sensitive p53 and NF-κB proteins in vitro and in vivo

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2020.01.011 ◽

2020 ◽

Vol 148 ◽

pp. 182-199

Author(s):

Mrityunjay Tyagi ◽

Ajay Kumar Bauri ◽

Subrata Chattopadhyay ◽

Birija Sankar Patro

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Cancer Cell Death

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Abstract 2050: Cell penetrating peptide, ST101, disrupts ATF5 regulation of anti-apoptotic Bcl-2 family proteins, resulting in induction of cancer cell death in vitro and tumor growth inhibition/regression in vivo

10.1158/1538-7445.sabcs18-2050 ◽

2019 ◽

Author(s):

Jim A. Rotolo ◽

Rick Ramirez ◽

Mark Koester ◽

Siok Leong ◽

Lila Ghamsari ◽

...

Keyword(s):

Cell Death ◽

Tumor Growth ◽

Growth Inhibition ◽

Cancer Cell ◽

Tumor Growth Inhibition ◽

Cell Penetrating Peptide ◽

Cancer Cell Death ◽

Cell Penetrating

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Involvement of general control nonderepressible kinase 2 in cancer cell apoptosis by posttranslational mechanisms

Molecular Biology of the Cell ◽

10.1091/mbc.e14-10-1438 ◽

2015 ◽

Vol 26 (6) ◽

pp. 1044-1057 ◽

Cited By ~ 10

Author(s):

Chen Wei ◽

Ma Lin ◽

Bian Jinjun ◽

Feng Su ◽

Cao Dan ◽

...

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Protein Level ◽

Cell Apoptosis ◽

General Control ◽

Screening Assay ◽

Cancer Cell Apoptosis ◽

Cancer Cell Death

General control nonderepressible kinase 2 (GCN2) is a promising target for cancer therapy. However, the role of GCN2 in cancer cell survival or death is elusive; further, small molecules targeting GCN2 signaling are not available. By using a GCN2 level-based drug screening assay, we found that GCN2 protein level critically determined the sensitivity of the cancer cells toward Na+,K+-ATPase ligand–induced apoptosis both in vitro and in vivo, and this effect was largely dependent on C/EBP homologous protein (CHOP) induction. Further analysis revealed that GCN2 is a short-lived protein. In A549 lung carcinoma cells, cellular β-arrestin1/2 associated with GCN2 and maintained the GCN2 protein level at a low level by recruiting the E3 ligase NEDD4L and facilitating consequent proteasomal degradation. However, Na+,K+-ATPase ligand treatment triggered the phosphorylation of GCN2 at threonine 899, which increased the GCN2 protein level by disrupting the formation of GCN2–β-arrestin–NEDD4L ternary complex. The enhanced GCN2 level, in turn, aggravated Na+,K+-ATPase ligand–induced cancer cell apoptosis. Our findings reveal that GCN2 can exert its proapoptotic function in cancer cell death by posttranslational mechanisms. Moreover, Na+,K+-ATPase ligands emerge as the first identified small-molecule drugs that can trigger cancer cell death by modulating GCN2 signaling.

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pH-Triggered burst intracellular release from hollow microspheres to induce autophagic cancer cell death

Journal of Materials Chemistry B ◽

10.1039/c5tb00328h ◽

2015 ◽

Vol 3 (48) ◽

pp. 9383-9396 ◽

Cited By ~ 10

Author(s):

Xin Liang ◽

Ying Yang ◽

Lijun Wang ◽

Xianbing Zhu ◽

Xiaowei Zeng ◽

...

Keyword(s):

Cell Death ◽

Cancer Cell ◽

Hollow Microspheres ◽

Cancer Cell Death ◽

Intracellular Release

Rapamycin–NaHCO3-loaded HMs combined CQ–NaHCO3-loaded HMs could efficiently induce cancer cell death through apoptosis with autophagosome both in vitro and in vivo.

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