AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway

• Published in: Molecular oncology 2016-05, Vol.10 (5), p.652-662
• Main Authors: Hrstka, Roman, Bouchalova, Pavla, Michalova, Eva, Matoulkova, Eva, Muller, Petr, Coates, Philip J., Vojtesek, Borivoj
• Format: Article
• Language: English
• Subjects: Adult; Aged; AGR2; Antineoplastic Agents - pharmacology; Breast; Breast - drug effects; Breast - metabolism; Breast - pathology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Cell cycle; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA damage; Drug resistance; Drug Resistance, Neoplasm; Dual-Specificity Phosphatases - metabolism; DUSP10; Enzyme Activation - drug effects; Estrogen receptors; Female; Gene amplification; Genetic transformation; Humans; Kinases; Lung cancer; MAP kinase; MDM2 protein; Medical prognosis; Menopause; Middle Aged; Mitogen-Activated Protein Kinase Phosphatases - metabolism; Mucoproteins; Mutation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oncogene Proteins; Oncoproteins; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; p53; p53 Protein; Phosphorylation; Prognosis; Proteins; Proteins - metabolism; Signal transduction; Signal Transduction - drug effects; Transcription; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2015.12.003

The tumor suppressor p53 plays a key role in malignant transformation and tumor development. However, the frequency of p53 mutations within individual types of cancer is different, suggesting the existence of other mechanisms attenuating p53 tumor suppressor activity. Changes in upstream regulators of p53 such as MDM2 amplification and overexpression, expression of viral oncoproteins, estrogen receptor signaling, or changes in p53 transcriptional target genes were previously described in wild-type p53 tumors. We identified a novel pathway responsible for attenuation of p53 activity in human cancers. We demonstrate that AGR2, which is overexpressed in a variety of human cancers and provides a poor prognosis, up-regulates DUSP10 which subsequently inhibits p38 MAPK and prevents p53 activation by phosphorylation. Analysis of human breast cancers reveals that AGR2 specifically provides a poor prognosis in ER+ breast cancers with wild-type p53 but not ER- or mutant p53 breast cancers, and analysis of independent data sets show that DUSP10 levels also have prognostic significance in this specific sub-group of patients. These data not only reveal a novel pro-oncogenic signaling pathway mediating resistance to DNA damaging agents in human tumors, but also has implications for designing alternative strategies for modulation of wild-type p53 activity in cancer therapy. •The transcription factor p53 is the most intensively studied tumor suppressor.•AGR2-dependent signaling pathway blocks wt p53 transcriptional activity.•p53 activity is impaired via DUSP10 up-regulation causing inhibition of p38 MAPK.•AGR2 signaling towards p53 was demonstrated both in vitro and in vivo.