title: Phosphorylation of interleukin (IL)-24 is required for mediating its anti-cancer activity.
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.
authors.affiliation: Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Janani
authors.initials: J
authors.lastname: Panneerselvam
authors.affiliation: Department of Thoracic & Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.|The University of Texas Dental School, Houston, Texas, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Shanker
authors.affiliation: Department of Thoracic & Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.|Department of Gastrointestinal Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Thoracic & Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.|Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Branch
authors.affiliation: Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Ranganayaki
authors.initials: R
authors.lastname: Muralidharan
authors.affiliation: Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Yan D
authors.initials: YD
authors.lastname: Zhao
authors.affiliation: DNASolve, Houston, Texas, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Chada
authors.affiliation: Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Munshi
authors.affiliation: Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.|Graduate Program in Biomedical Sciences, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Ramesh
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D004318:Doxycycline / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099180:Interleukin-24
chemical_list: D000900:Anti-Bacterial Agents; D004318:Doxycycline; D007378:Interleukins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D000099180:Interleukin-24; C546842:MTOR protein, human
keywords: IL-24; cytokine; lung cancer; phosphorylation