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  • br Protein acetylation Several reports show

    2019-07-11


    Protein acetylation Several reports show that MTX is able to induce acetylation of histones and other proteins. Extensive studies have established that histone acetylation is primarily associated with gene activation. Acetylation occurs at lysine residues on the amino-terminal tail of the protein molecule. This process is highly dynamic and is regulated by the opposing action of two enzyme families, histone acetyltransferases (HATs) and histone deacetylases (HDACs). Numerous correlative studies have demonstrated aberrant expression of HDACs in human tumors, and histone deacetylase inhibitors (HDACis) are used for treatment of many cancer diseases, such as thymoma, melanoma, B cell malignancies, various solid tumors, and cutaneous T-cell lymphoma [52]. Molecular modeling suggests that MTX is a potential histone deacetylase inhibitor (HDACi). The MTX molecule consists of a hydrophobic pteridine ring and a carboxylate-containing para-aminobenzoic caspase inhibitor tail similar to the structure of well-known HDACis such as trichostatin A, suberoylanilide hydroxamic acid (SAHA) and butyrate. This prediction was later confirmed, as MTX was shown to inhibit HDAC activity and to induce acetylation of histone H3 in A549 human lung carcinoma cells and in HeLa cervical carcinoma cells [55]. Moreover, MTX is able to increase the expression of E-cadherin through the downregulation of HDACs. This effect is associated with an inhibition of the expression of the methyltransferase enzyme enhancer of zeste homolog 2: this inhibitory effect was the same as observed after the treatment with SAHA [17]. In addition, MTX can have a positive impact on the accumulation of acetylated histone H3 in osteosarcoma cells [44]. Considering the acetylation of non-histone proteins, MTX induces an increase in p53 acetylation, and this effect is correlated with higher nuclear accumulation and stability of p53 [17]. Another study showed that treatment with MTX induces hyperacetylation of the transcription factor E2F1 in melanoma cells [36].
    Effects of MTX on other proteins Although many molecular mechanisms and targets of MTX have been identified so far, many others have yet to be revealed. Several recently published studies showed that MTX can even influence some protein kinases and other signaling proteins. For instance, MTX suppresses human JAK/STAT signaling without affecting other phosphorylation-dependent pathways. MTX significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human myeloproliferative neoplasms [48]. Another study showed that in human T-cell lines, MTX inhibits the activation of NF-κB via depletion of tetrahydrobiopterin and increases Jun-N-terminal kinase-dependent p53 activity. MTX also inhibits NF-κB activity in fibroblast-like synoviocytes via the release of adenosine and adenosine receptor activation [43]. In human skin fibroblasts, MTX induces an increase in phosphorylation of ERK1/2 and expression of MMP-1 through the ERK1/2 pathway [27]. These effects are not limited to human cells. Treatment of mice with MTX leads to the phosphorylation of AMP-activated protein kinase α, the induction of manganese superoxide dismutase in the aorta and the subsequently reduced expression of cell adhesion molecules [49]. Very recently, MTX was shown to induce posttranslational nitrosative modification of proteins; however, it is not known which target proteins are involved in this process [28].
    Dose effects of MTX treatment The diverse effects of MTX described above are apparently concentration-dependent. The non-DHFR effects summarized in this review are achievable using MTX concentrations detectable in human plasma during the treatment of oncologic patients, particularly the high-dose MTX treatment, which is defined as a dose >1g/m2 of body surface and contributes to high plasma concentrations of MTX. It has been shown that concentrations of MTX of approximately 40μM are reached during high-dose MTX treatments of pediatric solid tumors [29], [45], and MTX concentrations of 100μM or higher can be achieved in human plasma several hours after the administration of MTX in osteosarcoma patients [16]. However, the situation varies for other diseases as well as for low-dose MTX treatment [14]. For example, low-dose MTX is a standard regimen for the treatment of rheumatoid arthritis, and the maximum plasma concentration of MTX in rheumatoid arthritis patients who take an average MTX dosage of 7.2mg/week ranges from 0.04 to 0.38μM [40]. Therefore, it is important to reflect the concentrations of MTX that are needed to achieve a desired effect.