Tartrate-Resistant Acid Phosphatase 5/ACP5 Interacts with p53 to Control the Expression of SMAD3 in Lung Adenocarcinoma

Abstract

Tartrate-resistant acid phosphatase 5 (TRAP/ACP5) has been shown to involve the development and prognosis of multiple tumors in previous studies; however, the mechanism in lung cancer is still unclear, and thus this study investigated the role of ACP5 in the progression of lung adenocarcinoma. After a series of in vitro and in vivo experiments, we observed that ACP5 expression was increased in lung adenocarcinomas (40/ 69, 57.97%); importantly, an increased ACP5 level was associated with patient age (p = 0.044) and lymph node metastasis (p = 0.0385). ACP5 overexpression significantly enhanced A549 and NCI-H1975 cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) and reduced cell apoptosis. Knocking down the expression of ACP5 could rescue the above cell phenotypes. Furthermore, enhancing ACP5 expression promoted lung adenocarcinoma cell hyperplasia and intrapulmonary metastasis in a mouse model. Additionally, mechanistic studies revealed that ACP5 might regulate p53 phosphorylation at Ser392, thereby enhancing the ubiquitination of p53, which then underwent degradation. Reducing the levels of p53 intensified the transcription of SMAD3, which promotes EMT in lung adenocarcinoma cells. In summary, the present study provides a theoretical basis and important scientific evidence on the key role of ACP5 in lung adenocarcinoma progression by inducing EMT via the regulation of p53/ SMAD3 signaling.

The role of ubiquitination and deubiquitination in cancer metabolism

“…For instance, MAVS and ATF3 can stabilize p53 by preventing p53 from MDM2-mediated ubiquitination [186,187]. ACP5 mediated p53 phosphorylation enhanced the ubiquitination and degradation of p53 [188]. p53 protein can be deubiquitinated by DUB OTUD1, OTUD3, OTUD5, ATXN3, USP10, USP11, USP15, USP24, USP29 and USP42 to enhance its function as tumor suppressor under the conditions of high carcinogenicity and genotoxicity [117,[189][190][191][192][193][194][195][196][197][198].…”

Tartrate-resistant acid phosphatase 5 serves as a viable target against pulmonary fibrosis by modulating β-catenin signaling

“…Tartrate-Resistant Acid Phosphatase 5 (ACP5), also named purple acid phosphatase, which maps to chromosome 19p13.2, contains a binuclear iron center 13 . Previous studies, including ours, have demonstrated that ACP5 plays a critical role in the pathogenesis of tumors, such as lung adenocarcinoma 14 , colorectal cancer 15 , breast cancer 16 and hepatocellular carcinoma 17 . Given that IPF and cancer share several pathogenic pathways 18,19 , we hypothesize that ACP5 is involved in the pathogenesis of IPF.…”

“…Previous studies, including ours, have demonstrated that ACP5 is upregulated in the progression of carcinoma and regulates tumor cell proliferation, migration and apoptosis [14][15][16][17] . As pathways and risk factors are often shared by cancer and IPF, we detected the levels of ACP5 in sera and lung samples from IPF patients.…”

“…Immunoprecipitation was performed according to a previous protocol 14 . Anti-ACP5 and anti-β-Catenin antibodies were used to form immune complexes with the ACP5 and β-Catenin proteins in lysates that were immunoprecipitated with magnetic beads (Cell Signaling Technology, Danvers, MA, USA).…”

Identified GNGT1 and NMU as Combined Diagnosis Biomarker of Non-Small-Cell Lung Cancer Utilizing Bioinformatics and Logistic Regression

“…In addition, other factors such as air pollution, poor diet, occupational exposure, and hereditary factors have been reported in association with NSCLC in nonsmokers [ 14 – 16 ]. Over the past few years, newly developed cytotoxic agents, including paclitaxel, gemcitabine, and vinorelbine, have emerged to offer multiple therapeutic choices for patients with LUAD [ 17 – 20 ]. However, chemotherapy for advanced NSCLC is often considered ineffective or excessively toxic [ 21 – 23 ].…”