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.

Overexpression of IL-32 is a novel prognostic factor in patients with localized clear cell renal cell carcinoma

“…This in vitro study revealed that the inhibitory effect of IL-32 γ was due to blockade of the NK-κB and STAT3 pathways involved in tumor cell growth. Moreover, IL-32 γ transgenic mice models showed a decreased expression of antiapoptotic, cell proliferation, and tumor-producing genes such as cleaved caspase-3 and -9, bax, cyclin D, COX-2, and iNOS, whereas the expression of their target apoptotic genes such as BCL-2 and X-chromosome inhibitor of apoptosis protein was significantly increased (39). The findings of the two recent studies indicate that IL-32 has anticancer effects in human malignancies.…”

“…However, the overexpression of IL-32 inhibited the HPV-16 E7-mediated COX-2 activation pathway and, ultimately, exhibited anti-oncogenic effects (22). In the most recent study on IL-32 and human cancer, Oh et al studied the expression of IL-32 in colon cancer and malignant melanoma cells using xenograft nude mice inoculated with IL-32 γ-transfected malignant cells (39). They observed the inhibitory effect of IL-32 γ on the growth of both malignant cell types.…”

Interleukin-32 in Infection, Inflammation and Cancer Biology

“…Their gastric mucosa expresses higher levels of IL-32, as well as levels in sera of same patients. Opposite to these findings, there are several reports about inhibitory effects of IL-32 on cancer cell growth, especially via the NF-κB and STAT3 signaling (29). IL-32θ inhibited epithelial-mesenchymal transition (EMT), resulting in the suppression of migratory and invasive capabilities of HT29 colon cancer cells (74).…”

“…Earlier investigations concluded that IL-32 downstream signaling involved multiple pathways -NF-κB and p38 MAPK pathways, Erk1/2 and PI3 K/Akt pathways, and IL-32-exposed human macrophage-like THP-1 cells resulted in the phosphorylation of p300 and DAPK-1 (23,10,28,29). But until today it was not clear whether this cytokine acts on intra-or extracellular level.…”

IL32 expression in peripheral blood CD3+ cells from myelodysplastic syndromes patients

“…Furthermore, the role of IL-32 in the production of regulatory cytokines has been described: IL-32β interacts with PKCδ and C/EBPα, which results in the production of IL-10 [16], and IL-32γ is correlated with enhanced production of proinflammatory cytokines, such as IL-1β and IL-6 [17]. IL-32γ is also implicated in HIV immunosuppression [18] and tumoral growth inhibition [19]. The interaction between IL-32δ and IL-32β isoforms inhibits IL-10 production by IL-32β [20], which suggests that other interactions between IL-32 isoforms may explain their multifunctional role [21].…”