Scibetta Sofia, Pepe Giuseppe, Iuliano Marco, Iaiza Alessia, Palazzo Elisabetta, Quadri Marika, Boltje Thomas J, Fazi Francesco, Petrozza Vincenzo, Di Bartolomeo Sabrina, Di Pardo Alba, Calogero Antonella, Mangino Giorgio, Maglione Vittorio, Rosa Paolo
Department of Medical-Surgical Sciences and Biotechnologies, University of Rome "Sapienza", Polo Pontino, C.so della Repubblica 79, 04100 Latina, Italy.
IRCCS Neuromed, Via Dell'Elettronica, 86077 Pozzilli, Italy.
Int J Mol Sci. 2025 Aug 6;26(15):7625. doi: 10.3390/ijms26157625.
Glioblastoma (GBM) is a highly aggressive brain tumor marked by invasive growth and therapy resistance. Tumor cells adapt to hostile conditions, such as hypoxia and nutrient deprivation, by activating survival mechanisms including autophagy and metabolic reprogramming. Among GBM-associated changes, hypersialylation, particularly, the aberrant expression of polysialic acid (PSA), has been linked to increased plasticity, motility, and immune evasion. PSA, a long α2,8-linked sialic acid polymer typically attached to the NCAM, is abundant in the embryonic brain and re-expressed in cancers, correlating with poor prognosis. Here, we investigated how PSA expression was regulated in GBM cells under nutrient-limiting conditions. Serum starvation induced a marked increase in PSA-NCAM, driven by upregulation of the polysialyltransferase ST8SiaIV and an autophagy-dependent recycling of sialic acids from degraded glycoproteins. Inhibition of autophagy or sialidases impaired PSA induction, and PSA regulation appeared dependent on p53 function. Immunohistochemical analysis of GBM tissues revealed co-localization of PSA and LC3, particularly around necrotic regions. In conclusion, we identified a novel mechanism by which GBM cells sustain PSA-NCAM expression via autophagy-mediated sialic acid recycling under nutrient stress. This pathway may enhance cell migration, immune escape, and stem-like properties, offering a potential therapeutic target in GBM.
胶质母细胞瘤（GBM）是一种具有高度侵袭性的脑肿瘤，其特征为浸润性生长和治疗抵抗。肿瘤细胞通过激活包括自噬和代谢重编程在内的生存机制来适应低氧和营养剥夺等恶劣条件。在与GBM相关的变化中，高唾液酸化，特别是多唾液酸（PSA）的异常表达，与增加的可塑性、运动性和免疫逃逸有关。PSA是一种通常附着于神经细胞黏附分子（NCAM）的长链α2,8连接的唾液酸聚合物，在胚胎脑中含量丰富，并在癌症中重新表达，与预后不良相关。在此，我们研究了在营养限制条件下GBM细胞中PSA表达是如何被调控的。血清饥饿诱导PSA-NCAM显著增加，这是由多唾液酸转移酶ST8SiaIV的上调以及自噬依赖性地从降解的糖蛋白中回收唾液酸所驱动的。抑制自噬或唾液酸酶会损害PSA的诱导，并且PSA的调控似乎依赖于p53功能。对GBM组织的免疫组织化学分析显示PSA和LC3共定位，特别是在坏死区域周围。总之，我们确定了一种新机制，即GBM细胞在营养应激下通过自噬介导的唾液酸回收来维持PSA-NCAM的表达。该途径可能增强细胞迁移、免疫逃逸和干细胞样特性，为GBM提供了一个潜在的治疗靶点。
