Abstract
Malignant mesothelioma (MM) is an aggressive asbestos‐related cancer of the serous membranes. Despite intensive treatment regimens, MM is still a fatal disease, mainly due to the intrinsic resistance to current therapies and the lack of predictive markers and new valuable molecular targets. Protein arginine methyltransferase 5 (PRMT5) inhibition has recently emerged as a potential therapy against methylthioadenosine phosphorylase (MTAP)‐deficient cancers, in which the accumulation of the substrate 5'‐methylthioadenosine (MTA) inhibits PRMT5 activity, thus sensitizing the cells to further PRMT5 inhibition. Considering that the MTAP gene is frequently codeleted with the adjacent cyclin‐dependent kinase inhibitor 2A (CDKN2A) locus in MM, we assessed whether PRMT5 could represent a therapeutic target also for this cancer type. We evaluated PRMT5 expression, the MTAP status and MTA content in normal mesothelial and MM cell lines. We found that both administration of exogenous MTA and stable PRMT5 knock‐down, by short hairpin RNAs (shRNAs), selectively reduced the growth of MTAP‐deleted MM cells. We also observed that PRMT5 knock‐down in MTAP‐deficient MM cells reduced the expression of E2F1 target genes involved in cell cycle progression and of factors implicated in epithelial‐to‐mesenchymal transition. Therefore, PRMT5 targeting could represent a promising new therapeutic strategy against MTAP‐deleted MMs.
Highlights
Malignant mesothelioma (MM) is a very aggressive tumour of the serous membranes, with the most frequent type developing in the pleura, the membrane covering the lungs and lining the chest cavity
Recent advances in cancer metabolism research have identified molecular defects leading to vulnerabilities, which can be exploited therapeutically[42] These molecular alterations can represent biomarkers helping move towards personalized medicine
The same cells were analysed for matrix metallopeptidase 9 (MMP9) expression by real-time quantitative reverse transcription-PCR (qRT-PCR) MMP9 expression was calculated by the 2−ΔΔCt method relatively to parental cells
Summary
Malignant mesothelioma (MM) is a very aggressive tumour of the serous membranes, with the most frequent type developing in the pleura, the membrane covering the lungs and lining the chest cavity. Deletion on the short arm of chromosome 9, including the CDKN2A locus, is one of the first and most common mutations described in MM.[17] The discovery that CDKN2A deletion in cancer cells commonly involves codeletion of adjacent genes opened new perspectives in cancer research with a possible impact for MM18 It has observed that the methylthioadenosine phosphorylase (MTAP) gene, encoding a key enzyme in the adenosine and methionine salvage pathway from the substrate 5'-methylthioadenosine (MTA), is frequently codeleted with CDKN2A in different cancer types[19] including MM20,21 The MTAP gene has been suggested to be a tumour suppressor, the loss of which results in a higher cell invasive potential and poor prognosis for patients with different cancer types.[22] Importantly, MTAP loss determines the accumulation of the MTA substrate, a natural inhibitor of protein arginine methyltransferase 5 (PRMT5), generating a hypomorphic PRMT5 state in MTAP-deficient cancers that are, in this way, selectively sensitized to further PRMT5 inhibition This vulnerability can be exploited therapeutically, and PRMT5 targeting in MTAP-deficient cancers has become the focus of recent research.[23,24,25]. These considerations prompted us to investigate whether PRMT5 could be a valuable MM therapeutic target, the inhibition of which could impact on pathways fundamental for MM biology
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