The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China.
Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
Acta Pharmacol Sin. 2022 Nov;43(11):2977-2992. doi: 10.1038/s41401-022-00917-3. Epub 2022 May 17.
Glioblastoma (GBM), a malignant brain tumor, is a world-wide health problem because of its poor prognosis and high rates of recurrence and mortality. Apolipoprotein C1 (APOC1) is the smallest of apolipoproteins, implicated in many diseases. Recent studies have shown that APOC1 promotes tumorigenesis and development of several types of cancer. In this study we investigated the role of APOC1 in GBM tumorigenesis. Using in silico assays we showed that APOC1 was highly expressed in GBM tissues and its expression was closely related to GBM progression. We showed that APOC1 protein expression was markedly increased in four GBM cell lines (U251, U138, A172 and U87) compared to the normal brain glia cell lines (HEB, HA1800). In U251 cells, overexpression of APOC1 promoted cell proliferation, migration, invasion and colony information, which was reversed by APOC1 knockdown. APOC1 knockdown also markedly inhibited the growth of GBM xenografts in the ventricle of nude mice. We further demonstrated that APOC1 reduced ferroptosis by inhibiting KEAP1, promoting nuclear translocation of NRF2 and increasing expression of HO-1 and NQO1 in GBM cells. APOC1 also induced ferroptosis resistance by increasing cystathionine beta-synthase (CBS) expression, which promoted trans-sulfuration and increased GSH synthesis, ultimately leading to an increase in glutathione peroxidase-4 (GPX4). Thus, APOC1 plays a key role in GBM tumorigenesis, conferring resistance to ferroptosis, and may be a promising therapeutic target for GBM.
胶质母细胞瘤（GBM）是一种恶性脑肿瘤，由于其预后不良、复发率和死亡率高，成为全球性的健康问题。载脂蛋白 C1（APOC1）是载脂蛋白家族中最小的成员，与许多疾病有关。最近的研究表明，APOC1 促进了几种类型癌症的肿瘤发生和发展。在这项研究中，我们研究了 APOC1 在 GBM 肿瘤发生中的作用。通过计算机模拟实验，我们显示 APOC1 在 GBM 组织中高度表达，其表达与 GBM 进展密切相关。我们显示，与正常脑胶质细胞系（HEB、HA1800）相比，APOC1 蛋白在四种 GBM 细胞系（U251、U138、A172 和 U87）中的表达明显增加。在 U251 细胞中，APOC1 的过表达促进了细胞增殖、迁移、侵袭和集落形成，而 APOC1 的敲低则逆转了这一过程。APOC1 的敲低也显著抑制了裸鼠脑室中 GBM 异种移植瘤的生长。我们进一步证明，APOC1 通过抑制 KEAP1 减少铁死亡，促进 NRF2 的核易位，增加 HO-1 和 NQO1 的表达，从而减少 GBM 细胞中的铁死亡。APOC1 还通过增加胱硫醚-β-合酶（CBS）的表达来诱导铁死亡抵抗，这促进了转硫作用并增加了 GSH 的合成，最终导致谷胱甘肽过氧化物酶-4（GPX4）的增加。因此，APOC1 在 GBM 肿瘤发生中发挥关键作用，赋予铁死亡抵抗能力，可能是 GBM 的一个有前途的治疗靶点。
