A Paradoxical Effect of Interleukin-32 Isoforms on Cancer

Abstract

IL-32 plays a contradictory role such as tumor proliferation or suppressor in cancer development depending on the cancer type. In most cancers, it was found that the high expression of IL-32 was associated with more proliferative and progression of cancer. However, studying the isoforms of IL-32 cytokine has placed its paradoxical role into a wide range of functions based on its dominant isoform and surrounding environment. IL-32β, for example, was found mostly in different types of cancer and associated with cancer expansion. This observation is legitimate since cancer exhibits some hypoxic environment and IL-32β was known to be induced under hypoxic conditions. However, IL-32θ interacts directly with protein kinase C-δ reducing NF-κB and STAT3 levels to inhibit epithelial-mesenchymal transition (EMT). This effect could explain the different functions of IL-32 isoforms in cancer. However, pro- or antitumor activity which is dependant on obesity, gender, and age as it relates to IL-32 has yet to be studied. Obesity-related IL-32 regulation indicated the role of IL-32 in cancer metabolism and inflammation. IL-32-specific direction in cancer therapy is difficult to conclude. In this review, we address that the paradoxical effect of IL-32 on cancer is attributed to the dominant isoform, cancer type, tumor microenvironment, and genetic background. IL-32 seems to have a contradictory role in cancer. However, investigating multiple IL-32 isoforms could explain this doubt and bring us closer to using them in therapy.

Keywords: hypoxia; interleukin-32; metastasis; stromal tumor; tumor microenvironment.

Figure 1

Schematic illustration showing the effect of IL-32. (A) Schematic illustration showing the effect of IL-32 on the BMP pathway and IL-6 induction. In the presence of BMP4, it feeds the loop and binds to the BMP receptor, activating SMAD and thus regulating gene expression. IL-6 is inhibited by this regulation. On the other hand, in the presence of IL-32, IL-6 is induced and activates several pathways. One of these pathways is ERK, which in turn inhibits SMAD. Therefore, IL-6 induced by IL-32 acts as negative feedback for the BMP pathway, as results of cell proliferation increased. IL-32 was found to increase the expression (either directly or indirectly) of the connective tissue growth factor (cTGF), as results of spindle-shape transformation increased, and thus invasion and metastasis occurred. (B) Schematic illustration showing the different effects of IL-32 isoform in AML. IL-32γ was shown to induce TNF-α production and activate NF-κB and MAPK signaling pathways and therefore, increased proliferation and survival. Whereas, IL-32θ was shown to inhibit TNF-α and phosphorylated p38 MAPK and NF-κB, thus, reducing cancer progression. This makes IL-32θ to be considered a potent inhibitor of TNF-α in patients with AML. Figure created by BioRender App.

Figure 2

Schematic illustration showing cancer cell death by IL-32α in CML and lymphoma. Cancer cell death was reported when the IL-32α isoform is expressed in CML or lymphoma. This cancer inhibitory effect occurs through enhancing natural killer (NK) cell-mediated killing. PKCℇ inhibits apoptosis and the promotion of cell survival, by regulating several pathways, one of PKCℇ regulations is the activation of STAT3. IL-32α binds to PKCℇ and inhibits its functions and regulations. As a result, transcriptional modifications occurred including the downregulation of Bcl-6 and the upregulation of death receptors (ULBP2 and Fas receptor) resulting in NK cell-mediated killing by the stimulation of both Fas receptor and ULBP. ULBP is a ligand of NKG2D in NK. Figure created by BioRender App.

Figure 3

Schematic illustration showing the different effects of IL-32 isoform in cancer cells under hypoxic conditions. The elevated IL-32β interacts with PKCδ in tumor-promoting antiapoptotic signaling that increased cancer progression. On the contrary, IL-32θ interacts with PKCδ inhibiting its antiapoptotic effect and reduces NF-κB and STAT3, thus inhibiting epithelial-mesenchymal transition (EMT). Figure created by BioRender App.

Figure 4

Schematic illustration showing the range of signaling pathways that are activated by IL-32 and promoting cancer progression. In terms of angiogenesis, EMT, and metastasis. In brief, IL-32 promotes the Akt, NF-kB, STAT3 (which can be activated by PKC/CCL8), and integrin αVβ3 signaling cascades, each having different transcription modifications. Therefore, regulating the activity of several transcription factors play a role in cancer such as angiogenesis, EMT, and metastasis as well as αVβ3, VEGF, and HIF-α enhance angiogenesis. The ZEB1 or B-catenin enhances EMT. VEGF is also associated with EMT and metastasis. Additionally, the transcription of MMPs (like MMP2 and MMP9), Vimentin, Slug, and Snail promotes metastasis. Figure created by BioRender App.