Manfredelli Dominga, Torcoli Camilla, Pariano Marilena, Bellezza Guido, Baroni Tiziano, Talesa Vincenzo N, Sidoni Angelo, Antognelli Cinzia
Division of Biosciences and Medical Embryology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy.
Division of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, 06129 Perugia, Italy.
Antioxidants (Basel). 2025 Sep 15;14(9):1120. doi: 10.3390/antiox14091120.
Glyoxalase 1 (Glo1) functions as a catalyst that neutralizes methylglyoxal (MG), a highly reactive glycating agent predominantly produced during glycolysis-a metabolic pathway upregulated in cancer cells. MG primarily reacts with the amino groups of proteins (especially at arginine residues), leading to the formation of a major advanced glycation end product known as MG-derived hydroimidazolone 1 (MG-H1). We previously demonstrated in PC3 human prostate cancer (PCa) cells that the PTEN/PKM2/ERα axis promotes their aggressive phenotype by regulating the Glo1/MG-H1 pathway. In this study, after confirming our earlier findings, we investigated the downstream mechanisms of the PTEN/PKM2/ERα/Glo1/MG-H1 axis in controlling PC3 cell growth, focusing on the role of RAGE, a high-affinity receptor for MG-H1; hydrogen peroxide (HO); and Krev interaction trapped 1 (KRIT1), an emerging tumor suppressor. Using genetic approaches and specific inhibitors/scavengers, we demonstrated that the PTEN/PKM2/ERα/Glo1/MG-H1 axis promotes PC3 cell growth-measured by proliferation and etoposide-induced apoptosis resistance-through a mechanism involving MG-H1/RAGE pathway desensitization that leads to HO-mediated KRIT1 downregulation. These findings support and expand the role of PTEN signaling in PCa progression and shed light on novel mechanistic pathways driven by MG-dependent glycative stress, involving KRIT1, in this still incurable stage of the disease.
乙二醛酶1（Glo1）作为一种催化剂，可中和甲基乙二醛（MG），MG是一种高反应性糖基化剂，主要在糖酵解过程中产生，而糖酵解是癌细胞中上调的代谢途径。MG主要与蛋白质的氨基反应（尤其是在精氨酸残基处），导致形成一种主要的晚期糖基化终产物，称为MG衍生的氢咪唑酮1（MG-H1）。我们之前在PC3人前列腺癌（PCa）细胞中证明，PTEN/PKM2/ERα轴通过调节Glo1/MG-H1途径促进其侵袭性表型。在本研究中，在证实我们早期的发现后，我们研究了PTEN/PKM2/ERα/Glo1/MG-H1轴在控制PC3细胞生长中的下游机制，重点关注RAGE（MG-H1的高亲和力受体）、过氧化氢（HO）和Krev相互作用捕获1（KRIT1，一种新兴的肿瘤抑制因子）的作用。使用基因方法和特异性抑制剂/清除剂，我们证明PTEN/PKM2/ERα/Glo1/MG-H1轴通过一种涉及MG-H1/RAGE途径脱敏的机制促进PC3细胞生长（通过增殖和依托泊苷诱导的凋亡抗性来衡量），该机制导致HO介导的KRIT1下调。这些发现支持并扩展了PTEN信号在PCa进展中的作用，并揭示了在这种仍无法治愈的疾病阶段，由MG依赖性糖基化应激驱动的涉及KRIT1的新机制途径。
