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,
* Department of Pathology and Laboratory Medicine and
Department of Microbiology, Immunology, and Molecular Genetics, and
Markey Cancer Center, University of Kentucky, Lexington, KY 40536; and
Department of Oncology, Amgen, Seattle, WA 98101
Killer lymphocytes recognize stress-activated NKG2D ligands on tumors. We examined NKG2D ligand expression in head and neck squamous cell carcinoma (HNSCC) cells and other cell lines. HNSCC cells typically expressed MHC class I chain-related gene A (MICA), MICB, UL16-binding protein (ULBP)2, and ULBP3, but they were uniformly negative for cell surface ULBP1 and ULBP4. We then studied how cancer treatments affected NKG2D ligand expression. NKG2D ligand expression was not changed by most cancer-relevant treatments. However, bortezomib and other proteasome inhibitor drugs with distinct mechanisms of action dramatically and specifically up-regulated HNSCC ULBP1 mRNA and cell surface protein. Proteasome inhibition also increased RNA for ULBP1 and other NKG2D ligands in nontransformed human keratinocytes. Proteasome inhibitor drugs increased ULBP1 transcription by acting at a site in the 522-bp ULBP1 promoter. Although the DNA damage response pathways mediated by ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) signaling had been reported to up-regulate NKG2D ligand expression, we found that ULBP1 up-regulation was not inhibited by caffeine and wortmannin, inhibitors of ATM/ATR signaling. ULBP1 expression in HNSCC cells was not increased by several ATM/ATR activating treatments, including bleomycin, cisplatin, aphidicolin, and hydroxyurea. Ionizing radiation caused ATM activation in HNSCC cells, but high-level ULBP1 expression was not induced by gamma radiation or UV radiation. Thus, ATM/ATR signaling was neither necessary nor sufficient for high-level ULBP1 expression in human HNSCC cell lines and could not account for the proteasome effect. The selective induction of ULBP1 expression by proteasome inhibitor drugs, along with variable NKG2D ligand expression by human tumor cells, indicates that NKG2D ligand genes are independently regulated.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants DE11139 and AI050656 and the Kentucky Lung Cancer Research Program. J.E.B. was supported by National Institutes of Health Grant T32-CA09509.
2 Current address: Cargill, 1710 16th Street SE, Cedar Rapids, IA 52401.
3 Address correspondence and reprint requests to Dr. Charles T. Lutz, Department of Pathology and Laboratory Medicine, University of Kentucky, 800 Rose Street, MS 117, Lexington, KY 40536. E-mail address: charles.lutz{at}uky.edu
4 Abbreviations used in this paper: MICA, MHC class I chain-related gene A; ATM, ataxia-telangiectasia, mutated; ATR, ATM and Rad3-related; hnRNA, heteronuclear (unspliced) RNA; HNSCC, head and neck squamous cell carcinoma; MICB, MHC class I chain-related gene B; RAET, retinoic acid early transcript; ULBP, UL16-binding protein.
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