Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
PLoS One. 2024 Mar 21;19(3):e0300718. doi: 10.1371/journal.pone.0300718. eCollection 2024.
Malignant melanoma is the most aggressive form of skin cancer with a rather poor prognosis. Standard chemotherapy often results in severe side effects on normal (healthy) cells finally being difficult to tolerate for the patients. Shown by us earlier, cerium oxide nanoparticles (CNP, nanoceria) selectively killed A375 melanoma cells while not being cytotoxic at identical concentrations on non-cancerous cells. In conclusion, the redox-active CNP exhibited both prooxidative as well as antioxidative properties. In that context, CNP induced mitochondrial dysfunction in the studied melanoma cells via generation of reactive oxygene species (primarily hydrogen peroxide (H2O2)), but that does not account for 100% of the toxicity.
Cancer cells often show an increased glycolytic rate (Warburg effect), therefore we focused on CNP mediated changes of the glucose metabolism.
It has been shown before that glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity is regulated via oxidation of a cysteine in the active center of the enzyme with a subsequent loss of activity. Upon CNP treatment, formation of cellular lactate and GAPDH activity were significantly lowered. The treatment of melanoma cells and melanocytes with the GAPDH inhibitor heptelidic acid (HA) decreased viability to a much higher extent in the cancer cells than in the studied normal (healthy) cells, highlighting and supporting the important role of GAPDH in cancer cells.
We identified glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as a target protein for CNP mediated thiol oxidation.
恶性黑色素瘤是皮肤癌中最具侵袭性的一种，预后较差。标准化疗通常会对正常（健康）细胞产生严重的副作用，最终使患者难以耐受。我们之前的研究表明，氧化铈纳米粒子（CNP，纳米氧化铈）在相同浓度下对非癌细胞无细胞毒性，但选择性杀伤 A375 黑色素瘤细胞。总之，具有氧化还原活性的 CNP 表现出促氧化和抗氧化特性。在这种情况下，CNP 通过生成活性氧物种（主要是过氧化氢（H2O2））导致研究中的黑色素瘤细胞线粒体功能障碍，但这不能解释 100%的毒性。
癌细胞通常表现出更高的糖酵解率（瓦伯格效应），因此我们专注于 CNP 介导的葡萄糖代谢变化。
之前已经表明，甘油醛 3-磷酸脱氢酶（GAPDH）的活性通过酶活性中心的半胱氨酸氧化调节，随后活性丧失。在 CNP 处理后，细胞内乳酸和 GAPDH 活性明显降低。用 GAPDH 抑制剂 heptelidic 酸（HA）处理黑色素瘤细胞和黑素细胞，在癌细胞中比在研究的正常（健康）细胞中降低细胞活力的程度要高得多，这突出并支持了 GAPDH 在癌细胞中的重要作用。
我们确定甘油醛 3-磷酸脱氢酶（GAPDH）是 CNP 介导的巯基氧化的靶蛋白。
