Pibuel Matías Arturo, Poodts Daniela, Díaz Mariángeles, Molinari Yamila Azul, Franco Paula Gabriela, Hajos Silvia Elvira, Lompardía Silvina Laura
Instituto de Estudios de la Inmunidad Humoral (IDEHU)- CONICET; Departamento de Microbiología, Inmunología y Biotecnología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Capital Federal, Argentina.
Instituto de Estudios de la Inmunidad Humoral (IDEHU)- CONICET, Universidad de Buenos Aires, Capital Federal, Argentina.
Cell Death Discov. 2021 Oct 9;7(1):280. doi: 10.1038/s41420-021-00672-0.
The extracellular matrix plays a key role in cancer progression. Hyaluronan, the main glycosaminoglycan of the extracellular matrix, has been related to several tumor processes. Hyaluronan acts through the interaction with cell membrane receptors as CD44 and RHAMM and triggers signaling pathways as MEK/ERK. 4-methylumbelliferone (4MU), a well-known hyaluronan synthesis inhibitor, is a promising alternative for cancer therapy. 4MU is a coumarin derivative without adverse effects that has been studied in several tumors. However, little is known about its use in glioblastoma (GBM), the most malignant primary brain tumor in adults. Glioblastoma is characterized by fast growth, migration and tissue invasiveness, and a poor median survival of the patients after treatment. Several reports linked glioblastoma progression with HA levels and even with CD44 and RHAMM expression, as well as MEK/ERK activation. Previously, we showed on a murine GBM cell line that HA enhances GBM migration, while 4MU markedly inhibits it. In this work we showed for the first time, that 4MU decreases cell migration and induces senescence in U251 and LN229 human GBM cell lines. Furthermore, we observed that HA promotes GBM cell migration on both cell lines and that such effects depend on CD44 and RHAMM, as well as MEK/ERK signaling pathway. Interestingly, we observed that the exogenous HA failed to counteract the effects of 4MU, indicating that 4MU effects are independent of HA synthesis inhibition. We found that 4MU decreases total CD44 and RHAMM membrane expression, which could explain the effect of 4MU on cell migration. Furthermore, we observed that 4MU increases the levels of RHAMM inside the cell while decreases the nucleus/cytoplasm relation of p-ERK, associated with 4MU effects on cell proliferation and senescence induction. Overall, 4MU should be considered as a promising therapeutic alternative to improve the outcome of patients with GBM.
细胞外基质在癌症进展中起关键作用。透明质酸是细胞外基质的主要糖胺聚糖，与多种肿瘤进程相关。透明质酸通过与细胞膜受体如CD44和RHAMM相互作用发挥作用，并触发MEK/ERK等信号通路。4-甲基伞形酮（4MU）是一种著名的透明质酸合成抑制剂，是癌症治疗的一种有前景的替代方案。4MU是一种香豆素衍生物，无不良反应，已在多种肿瘤中进行研究。然而，关于其在胶质母细胞瘤（GBM）中的应用知之甚少，GBM是成人中最恶性的原发性脑肿瘤。胶质母细胞瘤的特征是生长迅速、迁移和组织侵袭性强，治疗后患者的中位生存期较差。几份报告将胶质母细胞瘤的进展与透明质酸水平甚至与CD44和RHAMM的表达以及MEK/ERK激活联系起来。此前，我们在小鼠胶质母细胞瘤细胞系中表明，透明质酸增强胶质母细胞瘤的迁移，而4MU则显著抑制它。在这项工作中，我们首次表明，4MU可减少U251和LN229人胶质母细胞瘤细胞系中的细胞迁移并诱导衰老。此外，我们观察到透明质酸促进这两种细胞系中的胶质母细胞瘤细胞迁移，且这种作用依赖于CD44和RHAMM以及MEK/ERK信号通路。有趣的是，我们观察到外源性透明质酸无法抵消4MU的作用，这表明4MU的作用独立于透明质酸合成抑制。我们发现4MU降低了总CD44和RHAMM的膜表达，这可以解释4MU对细胞迁移的影响。此外，我们观察到4MU增加了细胞内RHAMM的水平，同时降低了p-ERK的核/质比值，这与4MU对细胞增殖和衰老诱导的作用相关。总体而言，4MU应被视为改善胶质母细胞瘤患者预后的一种有前景的治疗选择。
