Role of MDA-7/IL-24 a Multifunction Protein in Human Diseases

Abstract

Subtraction hybridization identified genes displaying differential expression as metastatic human melanoma cells terminally differentiated and lost tumorigenic properties by treatment with recombinant fibroblast interferon and mezerein. This approach permitted cloning of multiple genes displaying enhanced expression when melanoma cells terminally differentiated, called melanoma differentiation associated (mda) genes. One mda gene, mda-7, has risen to the top of the list based on its relevance to cancer and now inflammation and other pathological states, which based on presence of a secretory sequence, chromosomal location, and an IL-10 signature motif has been named interleukin-24 (MDA-7/IL-24). Discovered in the early 1990s, MDA-7/IL-24 has proven to be a potent, near ubiquitous cancer suppressor gene capable of inducing cancer cell death through apoptosis and toxic autophagy in cancer cells in vitro and in preclinical animal models in vivo. In addition, MDA-7/IL-24 embodied profound anticancer activity in a Phase I/II clinical trial following direct injection with an adenovirus (Ad.mda-7; INGN-241) in tumors in patients with advanced cancers. In multiple independent studies, MDA-7/IL-24 has been implicated in many pathological states involving inflammation and may play a role in inflammatory bowel disease, psoriasis, cardiovascular disease, rheumatoid arthritis, tuberculosis, and viral infection. This review provides an up-to-date review on the multifunctional gene mda-7/IL-24, which may hold potential for the therapy of not only cancer, but also other pathological states.

Keywords: Cancer; Human diseases; Inflammation; MDA-7/IL-24.

Fig. 1

Schematic representation of MDA-7/IL-24 protein with predicted and established domains and protein modification sites indicated. Cleavage of the 49-amino acid signal peptide allows for secretion of the MDA-7/IL-24 protein. The IL-10 signature sequence is located between amino acids 101 and 121. N-glycosylation can occur at amino acids 85, 99, and 126. Protein kinase C consensus phosphorylation sites are present at amino acids 88, 133, and 161. Casein kinase II (CKII) consensus phosphorylation sites are present at amino acids 101, 111, and 161. Numbers indicate amino acids. Not drawn to scale. Figure reproduced from Menezes, M. E., Bhatia, S., Bhoopathi, P., Das, S. K., Emdad, L., Dasgupta, S., et al. (2014). MDA-7/IL-24: Multifunctional cancer killing cytokine. Advances in Experimental Medicine and Biology, 818, 127–153.

Fig. 2

Schematic representation of the splice isoforms of MDA-7/IL-24. Figure reproduced from Whitaker, E. L., Filippov, V., Filippova, M., Guerrero-Juarez, C. F., Duerksen-Hughes, P. J. (2011). Splice variants of mda-7/IL-24 differentially affect survival and induce apoptosis in U2OS cells. Cytokine, 56, 272–281.

Fig. 3

Schematic representation of the pathways regulated by MDA-7/IL-24. MDA-7/IL-24 regulates both pro- and antiapoptotic molecules to induce tumor-specific cell death. This involves a series of signaling events including downregulation of Mcl-1 and Bcl-xL and activation of tumor suppressors, i.e., SARI, PUMA, AIF, PERK, and others as shown in the figure. Also the cytokine induces ER stress and regulates a number of genes/proteins to block invasion and metastasis. MDA-7/IL-24 also modulates the immune pathways by deregulating a number of cytokines, which in turn activates the immune system to induce cytotoxic cell death.

Fig. 4

Model depicting the molecular mechanism of MDA-7/IL-24-mediated autophagy induction. MDA-7/IL-24 regulates autophagy mediated through ER stress and ceramide production. Also MDA-7/IL-24 downregulates miR-221, which in turn upregulates Beclin-1 to induce toxic autophagy leading to cell death. The transition of protective to toxic autophagy is mediated by the cleavage of ATG5 by Calpain.