title: Enhancement of NK cell-mediated lysis of non-small lung cancer cells by nPKC activator, ingenol 3,20 dibenzoate.
abstract: The IFN-γ production is crucial for NK cell-mediated lysis of cancer cells. Thus increasing the IFN-γ production by NK cells may be an ideal strategy to improve their tumoricidal effect. Since the focus on new drug development has shifted towards natural products, limited information is out there about natural products that enhance the IFN-γ production by NK cells. In this study, through a high-throughput screening, we have identified a natural product ingenol 3,20 dibenzoate (IDB), an activator of tumor suppressor protein kinase C (PKC) isozymes, could increase the IFN-γ production and degranulation by NK cells, especially when NK cells were stimulated by non-small lung cancer (NSCLC) cells. IDB also significantly enhanced the NK cell-mediated lysis of NSCLC cells. Furthermore, PKC inhibitor, sotrastaurin abrogated IDB-induced IFN-γ production, degranulation and cytotoxicity, but did not affect IFN-γ production by NK cells without IDB treatment and NSCLC cell stimulation. The IFN-γ neutralization reversed the IDB-induced enhancement of NK cell mediated killing. In conclusion, our study indicated that IDB enhanced NK cell-mediated lysis of NSCLC cells is dependent on specific PKC mediated IFN-γ production and degranulation. Thus, IDB may have a promising application in clinic for NK cell-based cancer immunotherapy.
authors.affiliation: Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd., Shanghai 201203, PR China.
authors.forename: Chenyuan
authors.initials: C
authors.lastname: Gong
authors.affiliation: Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd., Shanghai 201203, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yao
authors.affiliation: Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd., Shanghai 201203, PR China.
authors.forename: Zihang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd., Shanghai 201203, PR China.
authors.forename: Zhongya
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd., Shanghai 201203, PR China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd. Shanghai 201203, PR China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd., Shanghai 201203, PR China.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd. Shanghai 201203, PR China.
authors.forename: Wuxiong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd., Shanghai 201203, PR China; Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Rd. Shanghai 201203, PR China. Electronic address: zhushiguo@shutcm.edu.cn.
authors.forename: Shiguo
authors.initials: S
authors.lastname: Zhu
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000473:pathology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism
chemical_list: D004224:Diterpenes; C011875:ingenol dibenzoate; D007371:Interferon-gamma; D011493:Protein Kinase C
keywords: Antitumor; IFN-γ; Ingenol 3,20 dibenzoate; NK cells; PKC activator