Ramírez Eder, Jara Nery, Ferrada Luciano, Salazar Katterine, Martínez Fernando, Oviedo María José, Tereszczuk Joanna, Ramírez-Carbonell Sebastián, Vollmann-Zwerenz Arabel, Hau Peter, Nualart Francisco
Laboratory of Neurobiology and Stem Cells NeuroCellT, Department of Cellular Biology, Faculty of Biological Sciences, University of Concepcion, Concepcion, Chile.
Center for Advanced Microscopy CMA BIO-BIO, University of Concepcion, Concepcion, Chile.
Antioxid Redox Signal. 2022 Sep;37(7-9):538-559. doi: 10.1089/ars.2021.0089. Epub 2022 Apr 18.
Glioblastoma (GB) is one of the most aggressive brain tumors. These tumors modify their metabolism, increasing the expression of glucose transporters, GLUTs, which incorporate glucose and the oxidized form of vitamin C, dehydroascorbic acid (DHA). We hypothesized that GB cells preferentially take up DHA, which is intracellularly reduced and compartmentalized into the endoplasmic reticulum (ER), promoting collagen biosynthesis and an aggressive phenotype. Our results showed that GB cells take up DHA using GLUT1, while GLUT3 and sodium-dependent vitamin C transporter 2 (SVCT2) are preferably intracellular. Using a baculoviral system and reticulum-enriched extracts, we determined that SVCT2 is mainly located in the ER and corresponds to a short isoform. Ascorbic acid (AA) was compartmentalized, stimulating collagen IV secretion and increasing and cell migration. Finally, orthotopic xenografts induced in immunocompetent guinea pigs showed that vitamin C deficiency retained collagen, reduced blood vessel invasion, and affected glomeruloid vasculature formation, all pathological conditions associated with malignancy. We propose a functional role for vitamin C in GB development and progression. Vitamin C is incorporated into the ER of GB cells, where it favors the synthesis of collagen, thus impacting tumor development. Collagen secreted by tumor cells favors the formation of the glomeruloid vasculature and enhances perivascular invasion. . 37, 538-559.
胶质母细胞瘤（GB）是最具侵袭性的脑肿瘤之一。这些肿瘤会改变其代谢，增加葡萄糖转运蛋白（GLUTs）的表达，GLUTs可摄取葡萄糖和维生素C的氧化形式——脱氢抗坏血酸（DHA）。我们推测GB细胞优先摄取DHA，DHA在细胞内被还原并分隔在内质网（ER）中，促进胶原蛋白的生物合成和侵袭性表型。我们的结果表明，GB细胞利用GLUT1摄取DHA，而GLUT3和钠依赖性维生素C转运蛋白2（SVCT2）主要存在于细胞内。利用杆状病毒系统和富含内质网的提取物，我们确定SVCT2主要位于内质网中，且对应一种短异构体。抗坏血酸（AA）被分隔，刺激IV型胶原蛋白的分泌，增加细胞迁移。最后，在具有免疫活性的豚鼠中诱导的原位异种移植显示，维生素C缺乏会保留胶原蛋白、减少血管侵袭并影响肾小球样脉管系统的形成，所有这些病理状况都与恶性肿瘤相关。我们提出维生素C在GB的发生和发展中具有功能性作用。维生素C被纳入GB细胞的内质网中，在那里它有利于胶原蛋白的合成，从而影响肿瘤的发展。肿瘤细胞分泌的胶原蛋白有利于肾小球样脉管系统的形成并增强血管周围侵袭。 37, 538 - 559。
