1. Metabolic reprogramming of stromal fibroblasts through p62-mTORC1 signaling promotes inflammation and tumorigenesis.
- Author
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Valencia, Tania, Kim, Ji Young, Abu-Baker, Shadi, Moscat-Pardos, Jorge, Ahn, Christopher S, Reina-Campos, Miguel, Duran, Angeles, Castilla, Elias A, Metallo, Christian M, Diaz-Meco, Maria T, and Moscat, Jorge
- Subjects
Cell Line ,Tumor ,Fibroblasts ,Stromal Cells ,Animals ,Mice ,Inbred C57BL ,Mice ,Knockout ,Humans ,Mice ,Prostatic Intraepithelial Neoplasia ,Prostatic Neoplasms ,Cell Transformation ,Neoplastic ,Neoplasm Invasiveness ,Prostatic Hyperplasia ,Inflammation ,Multiprotein Complexes ,Glucose ,Amino Acids ,Adaptor Proteins ,Signal Transducing ,Proto-Oncogene Proteins c-myc ,Heat-Shock Proteins ,Inflammation Mediators ,Interleukin-6 ,Coculture Techniques ,Transfection ,Cell Communication ,Signal Transduction ,RNA Interference ,Energy Metabolism ,Oxidative Stress ,Time Factors ,Male ,PTEN Phosphohydrolase ,HEK293 Cells ,TOR Serine-Threonine Kinases ,Tumor Microenvironment ,Sequestosome-1 Protein ,Mechanistic Target of Rapamycin Complex 1 ,Oncology & Carcinogenesis ,Oncology and Carcinogenesis ,Neurosciences - Abstract
The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.
- Published
- 2014