title: Disruption of the ribosomal P complex leads to stress-induced autophagy.
abstract: The human ribosomal P complex, which consists of the acidic ribosomal P proteins RPLP0, RPLP1, and RPLP2 (RPLP proteins), recruits translational factors, facilitating protein synthesis. Recently, we showed that overexpression of RPLP1 immortalizes primary cells and contributes to transformation. Moreover, RPLP proteins are overexpressed in human cancer, with the highest incidence in breast carcinomas. It is thought that disruption of the P complex would directly affect protein synthesis, causing cell growth arrest and eventually apoptosis. Here, we report a distinct mechanism by which cancer cells undergo cell cycle arrest and induced autophagy when RPLP proteins are downregulated. We found that absence of RPLP0, RPLP1, or RPLP2 resulted in reactive oxygen species (ROS) accumulation and MAPK1/ERK2 signaling pathway activation. Moreover, ROS generation led to endoplasmic reticulum (ER) stress that involved the EIF2AK3/PERK-EIF2S1/eIF2α-EIF2S2-EIF2S3-ATF4/ATF-4- and ATF6/ATF-6-dependent arms of the unfolded protein response (UPR). RPLP protein-deficient cells treated with autophagy inhibitors experienced apoptotic cell death as an alternative to autophagy. Strikingly, antioxidant treatment prevented UPR activation and autophagy while restoring the proliferative capacity of these cells. Our results indicate that ROS are a critical signal generated by disruption of the P complex that causes a cellular response that follows a sequential order: first ROS, then ER stress/UPR activation, and finally autophagy. Importantly, inhibition of the first step alone is able to restore the proliferative capacity of the cells, preventing UPR activation and autophagy. Overall, our results support a role for autophagy as a survival mechanism in response to stress due to RPLP protein deficiency.
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Artero-Castro
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Mileidys
authors.initials: M
authors.lastname: Perez-Alea
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Feliciano
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Leal
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Genestar
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Castellvi
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Peg
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón Y Cajal
authors.affiliation: a Oncology and Pathology Group ; Pathology Department; Institut de Recerca Hospital Vall d'Hebron ; Barcelona , Spain.
authors.forename: Matilde E L
authors.initials: ME
authors.lastname: Lleonart
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology / Q000648:ultrastructure; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D010084:Oxidation-Reduction; D010641:Phenotype; D014176:Protein Biosynthesis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012269:Ribosomal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D012269:Ribosomal Proteins; D000111:Acetylcysteine
keywords: ER stress; ROS; RPLP proteins; RPLP0; RPLP1; RPLP2; UPR; autophagy; cancer