Search Results (6)

The MTAP (methylthioadenosine phosphorylase) gene, located on chromosome 9p21, plays a crucial role in the methionine salvage pathway and is frequently co-deleted with CDKN2A in various malignancies. Loss of MTAP expression leads to the accumulation of methylthioadenosine (MTA), which selectively inhibits protein arginine methyltransferase 5 (PRMT5) and creates a unique metabolic vulnerability in MTAP-deficient tumors. These alterations have emerged as promising therapeutic targets in precision oncology. Recent advances highlight the potential of exploiting MTAP loss through synthetic lethality approaches using PRMT5 and methionine adenosyltransferase 2A (MAT2A) inhibitors. Preclinical and early clinical data indicate that targeting these pathways can selectively impair tumor growth while sparing MTAP-proficient cells. Moreover, MTAP deletion has been associated with specific molecular and immunologic profiles that may influence treatment response and tumor microenvironment characteristics. This review summarizes current knowledge on the biological functions of MTAP, the mechanisms linking its loss to oncogenesis, and the evolving landscape of therapeutic strategies targeting MTAP-deficient cancers. Understanding these molecular dependencies offers novel opportunities for the development of precision-based therapies across diverse tumor types. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, characterized by a dismal prognosis and limited therapeutic options. Its highly invasive nature and pronounced intratumoral heterogeneity underscores the urgent need for innovative and targeted therapeutic strategies. One promising approach is synthetic lethality, which exploits cancer-specific genetic vulnerabilities to selectively eliminate tumor cells. A well-characterized example involves the deletion of methylthioadenosine phosphorylase (MTAP), commonly observed in GBM and other malignancies. This review focuses on synthetic lethality targeting protein arginine methyltransferase 5 (PRMT5) in MTAP-deleted GBM. Loss of MTAP leads to the accumulation of methylthioadenosine (MTA), a metabolite that partially inhibits PRMT5, thereby creating a selective vulnerability to PRMT5 inhibition which is used to inhibit the residual function of PRMT5. We critically evaluate preclinical and clinical data on both first- and second-generation PRMT5 inhibitors, with particular emphasis on MTA-cooperative compounds that selectively exploit MTAP deficiency. Despite promising anti-tumor activity in vitro, the clinical efficacy of PRMT5 inhibitors is often limited by the tumor microenvironment, particularly the impact of non-malignant cells that attenuate drug activity. Finally, we explore rational combination strategies that integrate PRMT5 inhibition with existing therapies to enhance clinical outcomes in GBM. Full article

Metabolite accumulation in the tumor microenvironment fosters immune evasion and limits the efficiency of immunotherapeutic approaches. Methylthioadenosine phosphorylase (MTAP), which catalyzes the degradation of 5′-deoxy-5′methylthioadenosine (MTA), is downregulated in many cancer entities. Consequently, MTA accumulates in the microenvironment of MTAP-deficient tumors, where it is known to inhibit tumor-infiltrating T cells and NK cells. However, the impact of MTA on other intra-tumoral immune cells has not yet been fully elucidated. To study the effects of MTA on dendritic cells (DCs), human monocytes were maturated into DCs with (MTA-DC) or without MTA (co-DC) and analyzed for activation, differentiation, and T cell-stimulating capacity. MTA altered the cytokine secretion profile of monocytes and impaired their maturation into dendritic cells. MTA-DCs produced less IL-12 and showed a more immature-like phenotype characterized by decreased expression of the co-stimulatory molecules CD80, CD83, and CD86 and increased expression of the monocyte markers CD14 and CD16. Consequently, MTA reduced the capability of DCs to stimulate T cells. Mechanistically, the MTA-induced effects on monocytes and DCs were mediated by a mechanism beyond adenosine receptor signaling. These results provide new insights into how altered polyamine metabolism impairs the maturation of monocyte-derived DCs and impacts the crosstalk between T and dendritic cells. Full article

Increasing evidence confirms that histone modification plays a critical role in preserving long-term immunological memory. Immune priming is a novel form of immunological memory recently verified in invertebrates. Toll-like receptor (TLR) signaling and cytokines have been reported to be involved in the immune priming of the Pacific oyster Crassostrea gigas. In the present study, the expression of Toll-like receptor 3 (CgTLR3), myeloid differentiation factor 88-2 (CgMyd88-2) and interleukin 17-1 (CgIL17-1) was found to be elevated in the hemocytes of C. gigas at 6 h after the secondary stimulation with Vibrio splendidus, which was significantly higher than that at 6 h after the primary stimulation (p < 0.05). A significant increase in histone H3 lysine 4 trimethylation (H3K4me3) enrichment was detected in the promoter region of the CgTLR3 gene at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05). After the treatment with a histone methyltransferase inhibitor (5′-methylthioadenosine, MTA), the level of H3K4me3 at the promoter of the CgTLR3 gene decreased significantly at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was significantly repressed at 6 h after the secondary stimulation with V. splendidus (p < 0.05). Conversely, the treatment with monomethyl fumarate (MEF, an inhibitor of histone demethylases) resulted in a significant increase in H3K4me3 enrichment levels at the CgTLR3 promoter at 7 d after the primary stimulation (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was observed to increase significantly at 6 h after the secondary stimulation (p < 0.05). These results suggested that H3K4me3 regulated MyD88-dependent TLR signaling in the hemocytes of C. gigas, which defined the role of histone modifications in invertebrate immune priming. Full article

We used an LC-MS/MS metabolomics approach to investigate one-carbon metabolism in the plasma of flaxseed-fed White Leghorn laying hens (aged 3.5 years). In our study, dietary flaxseed (via the activity of a vitamin B6 antagonist known as “1-amino d-proline”) induced at least 15-fold elevated plasma cystathionine. Surprisingly, plasma homocysteine (Hcy) was stable in flaxseed-fed hens despite such highly elevated cystathionine. To explain stable Hcy, our data suggest accelerated Hcy remethylation via BHMT and MS-B12. Also supporting accelerated Hcy remethylation, we observed elevated S-adenosylmethionine (SAM), an elevated SAM:SAH ratio, and elevated methylthioadenosine (MTA), in flaxseed-fed hens. These results suggest that flaxseed increases SAM biosynthesis and possibly increases polyamine biosynthesis. The following endpoint phenotypes were observed in hens consuming flaxseed: decreased physiological aging, increased empirical lifespan, 9–14% reduced body mass, and improved liver function. Overall, we suggest that flaxseed can protect women from ovarian tumor metastasis by decreasing omental adiposity. We also propose that flaxseed protects cancer patients from cancer-associated cachexia by enhancing liver function. Full article

Multiple factors involving the methionine salvage pathway (MSP) and polyamine biosynthesis have been found to be involved in cancer cell proliferation, migration, invasion and metastasis. This review summarizes the relationships of the MSP enzyme acireductone dioxygenase (ARD), the ADI1 gene encoding ARD and other gene products (ADI1GP) with carcinomas and carcinogenesis. ARD exhibits structural and functional differences depending upon the metal bound in the active site. In the penultimate step of the MSP, the Fe²⁺ bound form of ARD catalyzes the on-pathway oxidation of acireductone leading to methionine, whereas Ni²⁺ bound ARD catalyzes an off-pathway reaction producing methylthiopropionate and carbon monoxide, a biological signaling molecule and anti-apoptotic. The relationship between ADI1GP, MSP and polyamine synthesis are discussed, along with possible role(s) of metal in modulating the cellular behavior of ADI1GP and its interactions with other cellular components. Full article