Phosphorylation of interleukin (IL)-24 is required for mediating its anti-cancer activity
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Janani Panneerselvam1,4,*, Manish Shanker6,8,*, Jiankang Jin6,9,*, Cynthia D. Branch6,10, Ranganayaki Muralidharan1,4, Yan D. Zhao3,4, Sunil Chada7, Anupama Munshi2,4, Rajagopal Ramesh1,4,5
1Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
2Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
3Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
4Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
5Graduate Program in Biomedical Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
6Department of Thoracic & Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
7DNASolve, Houston, Texas, USA
8The University of Texas Dental School, Houston, Texas, USA
9Department of Gastrointestinal Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
10Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
*These authors have contributed equally to this work
Rajagopal Ramesh, e-mail: [email protected]
Keywords: IL-24, phosphorylation, lung cancer, cytokine
Received: March 27, 2015 Accepted: May 06, 2015 Published: May 18, 2015
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.
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