Radiation-induced matrix metalloproteinases limit natural killer cell-mediated anticancer immunity in NCI-H23 lung cancer cells.
Radiotherapy has been used to treat cancer for >100 years and is required by numerous patients with cancer. Ionizing radiation effectively inhibits the growth of cancer cells by inducing cell death and increasing anticancer immunity, through the induction of natural killer group 2 member D ligands (NKG2DLs); however, adverse effects have also been reported, including the promotion of metastasis. Matrix metalloproteinases (MMPs) are induced by ionizing radiation and have an important role in the invasion and metastasis of cancer cells. Previously, MMPs were demonstrated to increase the shedding of NKG2DLs, which may reduce the surface expression of NKG2DLs on cancer cells. As a consequence, the cancer cells may escape natural killer (NK)‑mediated anticancer immunity. In the present study, NCI‑H23 human non‑small cell lung cancer cells were used to investigate the combined effects of ionizing radiation and MMP inhibitors on the expression levels of NKG2DLs. Ionizing radiation increased the expression of MMP2 and ADAM metalloproteinase domain 10 protease, as well as NKG2DLs. The combined treatment of ionizing radiation and MMP inhibitors increased the surface expression levels of NKG2DLs and resulted in the increased susceptibility of the cancer cells to NK‑92 natural killer cells. Furthermore, soluble NKG2DLs were increased in the media by ionizing radiation and blocked by MMP inhibitors. The present study suggests that radiotherapy may result in the shedding of soluble NKG2DLs, through the induction of MMP2, and combined treatment with MMP inhibitors may minimize the adverse effects of radiotherapy.
Department of Biochemistry, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do 626-770, Republic of Korea.
Woong
W
Heo
Department of Biochemistry, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do 626-770, Republic of Korea.
Young Shin
YS
Lee
Department of Biochemistry, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do 626-770, Republic of Korea.
Cheol Hun
CH
Son
Department of Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Gijang 619-953, Republic of Korea.
Kwangmo
K
Yang
Department of Research Center, Dongnam Institute of Radiological and Medical Sciences, Busan, Gijang 619-953, Republic of Korea.
You Soo
YS
Park
Department of Biochemistry, Pusan National University School of Medicine, Yangsan, Gyeongsangnam-do 626-770, Republic of Korea.
Jaeho
J
Bae
D051722:ADAM Proteins / Q000235:genetics; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing
D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human