Campus de Vegazana s/n, Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Av. de Monforte de Lemos 5, 28029 Madrid, Spain.
Int J Mol Sci. 2021 Oct 29;22(21):11770. doi: 10.3390/ijms222111770.
Early acquisition of sorafenib resistance is responsible for the dismal prognosis of advanced hepatocarcinoma (HCC). Autophagy, a catabolic process involved in liver homeostasis, has been associated with chemosensitivity modulation. Forkhead box O3 (FOXO3) is a transcription factor linked to HCC pathogenesis whose role on autophagy-related sorafenib resistance remains controversial. Here, we unraveled the linkage between autophagy and sorafenib resistance in HCC, focusing on the implication of FOXO3 and its potential modulation by regorafenib. We worked with two HepG2-derived sorafenib-resistant HCC in vitro models (HepG2S1 and HepG2S3) and checked HCC patient data from the UALCAN database. Resistant cells displayed an enhanced basal autophagic flux compared to HepG2, showing higher autophagolysosome content and autophagy markers levels. Pharmacological inhibition of autophagy boosted HepG2S1 and HepG2S3 apoptosis and subG1 cells, but reduced viability, indicating the cytoprotective role of autophagy. HCC samples displayed higher FOXO3 levels, being associated with shorter survival and autophagic genes expression. Consistently, chemoresistant in vitro models showed significant FOXO3 upregulation. FOXO3 knockdown suppressed autophagy and caused resistant cell death, demonstrating that overactivation of such pro-survival autophagy during sorafenib resistance is FOXO3-dependent; a cytoprotective mechanism that the second-line drug regorafenib successfully abolished. Therefore, targeting FOXO3-mediated autophagy could significantly improve the clinical efficacy of sorafenib.
早期获得索拉非尼耐药是导致晚期肝癌（HCC）预后不良的原因。自噬是一种参与肝脏内稳态的分解代谢过程，与化疗敏感性调节有关。叉头框 O3（FOXO3）是与 HCC 发病机制相关的转录因子，其在自噬相关索拉非尼耐药中的作用仍存在争议。在这里，我们揭示了 HCC 中自噬与索拉非尼耐药之间的联系，重点研究了 FOXO3 的作用及其被regorafenib 潜在调节的作用。我们使用了两种源自 HepG2 的索拉非尼耐药 HCC 体外模型（HepG2S1 和 HepG2S3），并检查了 UALCAN 数据库中的 HCC 患者数据。耐药细胞与 HepG2 相比表现出增强的基础自噬通量，显示出更高的自噬溶酶体含量和自噬标记物水平。自噬的药理学抑制增强了 HepG2S1 和 HepG2S3 的细胞凋亡和亚 G1 细胞，但降低了细胞活力，表明自噬具有细胞保护作用。HCC 样本显示出更高的 FOXO3 水平，与较短的生存时间和自噬基因表达相关。一致地，化学耐药性体外模型显示出显著的 FOXO3 上调。FOXO3 敲低抑制自噬并导致耐药细胞死亡，表明在索拉非尼耐药期间，这种促进生存的自噬过度激活是 FOXO3 依赖性的；二线药物regorafenib 成功消除了这种细胞保护机制。因此，靶向 FOXO3 介导的自噬可能显著提高索拉非尼的临床疗效。
