GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner
Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthas...
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doaj-353225454ed9474787ab42266fa78fbb2021-04-09T23:04:46ZengMDPI AGCancers2072-66942021-04-01131802180210.3390/cancers13081802GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent MannerNayoung Kim0Mi Yeon Kim1Woo Seon Choi2Eunbi Yi3Hyo Jung Lee4Hun Sik Kim5Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul 05505, KoreaDepartment of Biomedical Sciences, Microbiology, University of Ulsan College of Medicine, Seoul 05505, KoreaDepartment of Biomedical Sciences, Microbiology, University of Ulsan College of Medicine, Seoul 05505, KoreaDepartment of Biomedical Sciences, Microbiology, University of Ulsan College of Medicine, Seoul 05505, KoreaDepartment of Biomedical Sciences, Microbiology, University of Ulsan College of Medicine, Seoul 05505, KoreaDepartment of Biomedical Sciences, Microbiology, University of Ulsan College of Medicine, Seoul 05505, KoreaNatural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.https://www.mdpi.com/2072-6694/13/8/1802natural killer cellGSK-3αNKG2DNKp30BCR-ABL1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nayoung Kim Mi Yeon Kim Woo Seon Choi Eunbi Yi Hyo Jung Lee Hun Sik Kim |
spellingShingle |
Nayoung Kim Mi Yeon Kim Woo Seon Choi Eunbi Yi Hyo Jung Lee Hun Sik Kim GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner Cancers natural killer cell GSK-3α NKG2D NKp30 BCR-ABL1 |
author_facet |
Nayoung Kim Mi Yeon Kim Woo Seon Choi Eunbi Yi Hyo Jung Lee Hun Sik Kim |
author_sort |
Nayoung Kim |
title |
GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner |
title_short |
GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner |
title_full |
GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner |
title_fullStr |
GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner |
title_full_unstemmed |
GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner |
title_sort |
gsk-3α inhibition in drug-resistant cml cells promotes susceptibility to nk cell-mediated lysis in an nkg2d- and nkp30-dependent manner |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-04-01 |
description |
Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner. |
topic |
natural killer cell GSK-3α NKG2D NKp30 BCR-ABL1 |
url |
https://www.mdpi.com/2072-6694/13/8/1802 |
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