PAGE4 promotes prostate cancer cells survive under oxidative stress through modulating MAPK/JNK/ERK pathway

Abstract

BackgroundProstate cancer (PCa) is one of the most common cancers in male worldwide. Oxidative stress has been recognized as one of the driving signals pathologically linked to PCa progression. Nevertheless, the association of oxidative stress with PCa progression remains unclear.MethodsWestern blot, q-RT-PCR and bioinformatics analyses were used to examine PAGE4 expression. Comet assay and Annexin V/ PI dual staining assay were performed to investigate DNA damage and cell death under oxidative stress. Mouse xenograft model of PCa cells was established to verify the role of PAGE4 in vivo. Transcriptomic analysis was performed to investigate the underlying mechanism for the function of PAGE4 under oxidative stress. Western blot assay was conducted to determine the status of MAPK pathway. Immunohistochemistry was used to identify protein expression of PAGE4 in tumor tissues.ResultsIn this study, we found that PAGE4 expression was increased in PCa cells under oxidative stress condition. PAGE4 overexpression protected PCa cells from oxidative stress-inducing cell death by reducing DNA damage. PAGE4 overexpression promoted PCa cells growth in vivo. Mechanistically, PAGE4 promoted the survival of prostate cancer cells through regulating MAPK pathway which reflected in decreasing the phosphorylation of MAP2K4, JNK and c-JUN but increasing phosphorylation of ERK1/2.ConclusionOur findings indicate that PAGE4 protects PCa cells from DNA damage and apoptosis under oxidative stress by modulating MAPK signalling pathway. PAGE4 expression may serve as a prognostic biomarker for clinical applications.Electronic supplementary materialThe online version of this article (10.1186/s13046-019-1032-3) contains supplementary material, which is available to authorized users.

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“…The MAPK/ERK signaling pathway is mainly related to cell proliferation and differentiation, while the MAPK/JNK and MAPK/p38 pathways are closely related to apoptosis of cells 23 . Activation of MAPK/ERK signaling pathway promotes the growth of prostate cancer 24 , cervical cancer 25 , thyroid cancer 26 , and breast cancer 27 . MAPK/ERK-induced epithelial-mesenchymal transition promotes migration and metastasis of lung cancer cells 28 .…”

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“…6 Furthermore, treatment with H 2 O 2 significantly increased the expression of PAGE4 in PCa cells, which protected cells from apoptosis, potentially through modulating mitogen-activated protein kinase pathway. 12 Finally, multiple studies have reported that, at least at the RNA level, PAGE4 is undetectable in metastatic PCa. 7,10,11,13 The significance of PAGE4 in PCa development and progression is highlighted by the fact that (a) expression of PAGE4messenger RNA (mRNA) is inversely correlated with Gleason score, 11 (b) decreased expression of PAGE4-mRNA in patients with PCa predicts an increased risk of biological recurrence, 10 and (c) PAGE4 levels correlate positively with, and predict survival of, patients with hormone-naive PCa.…”

A high glucose concentration is well tolerated by colorectal adenocarcinoma and melanoma cells but toxic to normal human gingival fibroblast: Results of an in vitro investigation

“…A study has reported that, under the oxidative stress condition, the prostate-associated gene 4 (PAGE4) expression also increases, which subsequently avoids cancer cell apoptosis. 18 PAGE4 is a highly intrinsically disordered protein, whereas protein overexpression could protect the cells from stress-induced death. 19 Another study has reported that cancer cells can ignore the signals that are important for preventing cell division or the beginning of a process known as "programmed cell death," whereby the body tends to dispose of its abnormal cells by increasing CD47 production.…”