title: IL-32γ inhibits cancer cell growth through inactivation of NF-κB and STAT3 signals.
abstract: Several studies have shown physiological functions of interleukin (IL)-32, a novel cytokine. However, the role of IL-32 in cancer development has not been reported. In this study, we showed that IL-32γ inhibited tumor growth in IL-32γ-overexpressing transgenic mice inoculated with melanoma as well as colon tumor growth in xenograft nude mice inoculated with IL-32γ-transfected colon cancer cells (SW620). The inhibitory effect of IL-32γ on tumor growth was associated with the inhibition of constitutive activated nuclear transcription factor-κB (NF-κB) and of signal transducer and activator of transcription 3 (STAT3). The expression of antiapoptotic, cell proliferation and tumor-promoting genes (bcl-2, X-chromosome inhibitor of apoptosis protein (IAP), cellular IAP and cellular FADD-like IL-1β-converting enzyme-inhibitory protein, cyclin D), cyclin-dependent kinase 4, cycolooxygenase-2 and inducible nitric oxide synthase was decreased, whereas the expression of apoptotic target genes (caspase-3 and -9, bax) increased. In tumor, spleen and blood, the number of cytotoxic CD8(+) T cells and CD57(+) natural killer cells and the levels of IL-10 increased, but that of tumor necrosis factor-α (TNF-α), IL-1β and IL-6 decreased. We also found that forced overexpression of IL-32γ inhibited colon cancer cell (SW620 and HCT116) growth accompanied with the inhibition of activated NF-κB and STAT3 in vitro. In addition, when IL-32γ was knocked down by small interfering RNA (siRNA) or neutralized with an anti-IL-32γ antibody, IL-32γ-induced colon cancer cell growth inhibition, the IL-32γ-induced decrease of TNF-α, IL-1 and IL-6 production, and the increase of IL-10 production were abolished. However, siRNA of NF-κB and STAT3 augmented IL-32γ-induced colon cancer cell growth inhibition. These findings indicate significant pathophysiological roles of IL-32γ in cancer development.
authors.affiliation: College of Pharmacy and Medical Research Center, Chungbuk National University, Chungbuk, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Oh
authors.forename: M-C
authors.initials: MC
authors.lastname: Cho
authors.forename: J-H
authors.initials: JH
authors.lastname: Kim
authors.forename: S Y
authors.initials: SY
authors.lastname: Lee
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.forename: E S
authors.initials: ES
authors.lastname: Park
authors.forename: J O
authors.initials: JO
authors.lastname: Ban
authors.forename: J-W
authors.initials: JW
authors.lastname: Kang
authors.forename: D-H
authors.initials: DH
authors.lastname: Lee
authors.forename: J-H
authors.initials: JH
authors.lastname: Shim
authors.forename: S B
authors.initials: SB
authors.lastname: Han
authors.forename: D C
authors.initials: DC
authors.lastname: Moon
authors.forename: Y H
authors.initials: YH
authors.lastname: Park
authors.forename: D-Y
authors.initials: DY
authors.lastname: Yu
authors.forename: J-M
authors.initials: JM
authors.lastname: Kim
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: D-Y
authors.initials: DY
authors.lastname: Yoon
authors.forename: J T
authors.initials: JT
authors.lastname: Hong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016207:Cytokines; C496971:IL32 protein, human; D007378:Interleukins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor