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IL-32? inhibits cancer cell growth through inactivation of NF-?B 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-32? inhibited tumor growth in IL-32?-overexpressing transgenic mice inoculated with melanoma as well as colon tumor growth in xenograft nude mice inoculated with IL-32?-transfected colon cancer cells (SW620). The inhibitory effect of IL-32? on tumor growth was associated with the inhibition of constitutive activated nuclear transcription factor-?B (NF-?B) 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-1?-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-? (TNF-?), IL-1? and IL-6 decreased. We also found that forced overexpression of IL-32? inhibited colon cancer cell (SW620 and HCT116) growth accompanied with the inhibition of activated NF-?B and STAT3 in vitro. In addition, when IL-32? was knocked down by small interfering RNA (siRNA) or neutralized with an anti-IL-32? antibody, IL-32?-induced colon cancer cell growth inhibition, the IL-32?-induced decrease of TNF-?, IL-1 and IL-6 production, and the increase of IL-10 production were abolished. However, siRNA of NF-?B and STAT3 augmented IL-32?-induced colon cancer cell growth inhibition. These findings indicate significant pathophysiological roles of IL-32? in cancer development.

SUBMITTER: Oh JH

PROVIDER: S-EPMC3145890 | biostudies-other | 2011 Jul

REPOSITORIES: biostudies-other

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IL-32γ inhibits cancer cell growth through inactivation of NF-κB and STAT3 signals.

Oh J H JH Cho M-C MC Kim J-H JH Lee S Y SY Kim H J HJ Park E S ES Ban J O JO Kang J-W JW Lee D-H DH Shim J-H JH Han S B SB Moon D C DC Park Y H YH Yu D-Y DY Kim J-M JM Kim S H SH Yoon D-Y DY Hong J T JT

Oncogene 20110321 30

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 constit ...[more]

PMID: 21423208

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Project description:Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing immune/inflammatory cells. The exact contribution of each immune cell subset and cytokine in the activation of the intracellular pathways sustaining CRC cell growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs) and lamina propria mononuclear cells (LPMCs) from the tumor area and the macroscopically unaffected, adjacent, colonic mucosa of patients who underwent resection for sporadic CRC and show that the culture supernatants of TILs, but not of LPMCs, potently enhance the growth of human CRC cell lines through the activation of the oncogenic transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization of immune cell complexity of TILs and LPMCs reveals no differences in the percentages of T cells, natural killer T cells, natural killer (NK) cells, macrophages and B cells. However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-? (TNF-?) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-? or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and TNF-?, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A, IL-21, IL-22, TNF-? and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation. Mice therapeutically given BP-1-102, an orally bioavailable compound targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon tumorigenesis and diminished expression of STAT3/NF-kB-activating cytokines in the neoplastic areas. These data suggest that strategies aimed at the cotargeting of STAT3/NF-kB activation and interaction between them might represent an attractive and novel approach to combat CRC.

Dataset Information

IL-32? inhibits cancer cell growth through inactivation of NF-?B and STAT3 signals.

Publications

IL-32γ inhibits cancer cell growth through inactivation of NF-κB and STAT3 signals.

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