Apoptosis and autophagy play seminal roles in maintaining organ homeostasis. Apoptosis represents canonical type I programmed cell death. Autophagy is viewed as pro-survival, however, excessive autophagy can promote type II cell death. Defective regulation of these two obligatory cellular pathways is linked to various diseases, including
cancer. Biologic or chemotherapeutic agents, which can reprogram
cancer cells to undergo apoptosis- or toxic autophagy-mediated cell death, are considered effective tools for treating
cancer.
Melanoma differentiation associated gene-7 (mda-7) selectively promotes these effects in
cancer cells. mda-7 was identified more than two decades ago by subtraction hybridization showing elevated expression during induction of terminal differentiation of metastatic
melanoma cells following treatment with recombinant
fibroblast interferon and
mezerein (a PKC activating agent). MDA-7 was classified as a member of the
IL-10 gene family based on its chromosomal location, and the presence of an
IL-10 signature motif and a secretory sequence, and re-named
interleukin-24 (MDA-7/IL-24). Multiple studies have established MDA-7/IL-24 as a potent anti-
cancer agent, which when administered at supra-physiological levels induces growth arrest and cell death through apoptosis and toxic autophagy in a wide variety of
tumor cell types, but not in corresponding normal/non-transformed cells. Furthermore, in a phase I/II clinical trial, MDA-7/IL-24 administered by means of a non-replicating adenovirus was well tolerated and displayed significant clinical activity in patients with multiple advanced
cancers. This review examines our current comprehension of the role of MDA-7/IL-24 in mediating
cancer-specific cell death via apoptosis and toxic autophagy.