Abstract
Interleukin (IL)-24 is a tumor suppressor/cytokine gene that undergoes post-translational modifications (PTMs). Glycosylation and ubiquitination are important for IL-24 protein stabilization and degradation respectively. Little is known about IL-24 protein phosphorylation and its role in IL-24-mediated anti-tumor activities. In this study we conducted molecular studies to determine whether IL-24 phosphorylation is important for IL-24-mediated anti-cancer activity.Human H1299 lung tumor cell line that was stably transfected with a doxycycline (DOX)-inducible (Tet-on) plasmid vector carrying the cDNA of IL-24-wild-type (IL-24wt) or IL-24 with all five phosphorylation sites replaced (IL-24mt) was used in the present study. Inhibition of tumor cell proliferation, cell migration and invasion, and induction of G2/M cell cycle arrest was observed in DOX-induced IL-24wt-expressing cells but not in IL-24mt-expressing cells. Secretion of IL-24mt protein was greatly reduced compared to IL-24wt protein. Further, IL-24wt and IL-24mt proteins markedly differed in their subcellular organelle localization. IL-24wt but not IL-24mt inhibited the AKT/mTOR signaling pathway. SiRNA-mediated AKT knockdown and overexpression of myristolyated AKT protein confirmed that IL-24wt but not IL-24mt mediated its anti-cancer activity by inhibiting the AKT signaling pathway.Our results demonstrate that IL-24 phosphorylation is required for inhibiting the AKT/mTOR signaling pathway and exerting its anti-cancer activities.
Highlights
Interleukin (IL)-24 is a novel tumor suppressor and a member of the IL-10 cytokine superfamily [1, 2]
Endogenous IL-24 protein expression is detectable in the peripheral blood mononuclear cells (PBMCs), T- and B-cells and in melanocytes [2, 3]
Since exogenous IL-24wt protein expression is detectable in the cytoplasm, endoplasmic reticulum (ER), and secretory organelles [3, 13, 14], we investigated whether phosphorylation affected IL-24 cellular localization
Summary
Interleukin (IL)-24 is a novel tumor suppressor and a member of the IL-10 cytokine superfamily [1, 2]. Endogenous IL-24 protein expression is detectable in the peripheral blood mononuclear cells (PBMCs), T- and B-cells and in melanocytes [2, 3]. IL-24 protein expression is lost in a majority of cancer cells of human origin [1, 2,3,4]. Previous studies from our laboratory and others have demonstrated that IL-24 has anti-tumor, anti-metastatic, and anti-angiogenic activities [3,4,5,6,7,8]. Studies have shown that IL-24 is a pro-inflammatory cytokine and stimulates the Th1-type immune response [2, 9], and is subject to post-translational modifications (PTMs), including phosphorylation, glycosylation, and ubiquitination [9,10,11]. Whether phosphorylation is required for IL-24-mediated antitumor activities is unknown
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