Quercetin enhances susceptibility to NK cell-mediated lysis of tumor cells through induction of NKG2D ligands and suppression of HSP70.
It is known that treatments with heat shock, some anticancer drugs, and ionizing radiation increase the expression of heat-shock proteins (HSPs) and natural killer group 2D (NKG2D) ligands in tumor cells. The increased HSPs may make the tumor cells resistant to apoptosis and reduction of HSPs may make the tumor cells more susceptible to natural killer (NK)-cell mediated lysis of tumor cells. In this study, we investigated whether quercetin which has inhibitory activities against heat-shock factor, protein kinase C, nuclear factor-kappaB, and phosphatidyl inositol 3-kinase, can modulate the expression of NKG2D ligands and suppress the HSPs in tumor cells. The results of this study showed that quercetin significantly induced the expression of several NKG2D ligands including major histocompatibility complex class I-related chain B, UL16-binding protein 1, and UL16-binding protein 2 in K562, SNU1, and SNU-C4 cells. The quercetin-treated K562, SNU1, and SNU-C4 cells showed an enhanced susceptibility to NK-92 cells through induction of NKG2D ligands. This increased expression of NKG2D ligands seemed to be due to the inhibition of the nuclear factor-kappaB and phosphatidyl inositol 3-kinase pathways. The findings of this study suggest that the induced NKG2D ligands with the decrease of HSP70 protein by quercetin may provide an attractive strategy to improve the effectiveness of NK cell-based cancer immunotherapy.
Bae
Jae-Ho
JH
Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea.
Kim
Joo-Young
JY
Kim
Mi-Ju
MJ
Chang
Sung-Ho
SH
Park
You-Soo
YS
Son
Cheol-Hun
CH
Park
Soo-Jung
SJ
Chung
Joo-Seop
JS
Lee
Eun-Yup
EY
Kim
Sun-Hee
SH
Kang
Chi-Dug
CD
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D058851:GPI-Linked Proteins; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000975:Antioxidants; D058851:GPI-Linked Proteins; D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C094840:MR1 protein, human; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; D011794:Quercetin; D019869:Phosphatidylinositol 3-Kinases