Institute of Pathology, University of Bern, Bern, Switzerland.
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
PLoS One. 2018 Jun 13;13(6):e0197610. doi: 10.1371/journal.pone.0197610. eCollection 2018.
Paclitaxel is a powerful chemotherapeutic drug, used for the treatment of many cancer types, including esophageal adenocarcinomas (EAC). Autophagy is a lysosome-dependent degradation process maintaining cellular homeostasis. Defective autophagy has been implicated in cancer biology and therapy resistance. We aimed to assess the impact of autophagy on chemotherapy response in EAC, with a special focus on paclitaxel. Responsiveness of EAC cell lines, OE19, FLO-1, OE33 and SK-GT-4, to paclitaxel was assessed using Alamar Blue assays. Autophagic flux upon paclitaxel treatment in vitro was assessed by immunoblotting of LC3B-II and quantitative assessment of WIP1 mRNA. Immunohistochemistry for the autophagy markers LC3B and p62 was applied on tumor tissue from 149 EAC patients treated with neoadjuvant chemotherapy, including pre- and post-therapeutic samples (62 matched pairs). Tumor response was assessed by histology. For comparison, previously published data on 114 primary resected EAC cases were used. EAC cell lines displayed differing responsiveness to paclitaxel treatment; however this was not associated with differential autophagy regulation. High p62 cytoplasmic expression on its own (p ≤ 0.001), or in combination with low LC3B (p = 0.034), was associated with nonresponse to chemotherapy, regardless of whether or not the regiments contained paclitaxel, but there was no independent prognostic value of LC3B or p62 expression patterns for EAC after neoadjuvant treatment. p62 and related pathways, most likely other than autophagy, play a role in chemotherapeutic response in EAC in a clinical setting. Therefore p62 could be a novel therapeutic target to overcome chemoresistance in EAC.
紫杉醇是一种强效的化疗药物，用于治疗多种癌症类型，包括食管腺癌（EAC）。自噬是一种溶酶体依赖性降解过程，维持细胞内稳态。自噬缺陷与癌症生物学和治疗耐药性有关。我们旨在评估自噬对 EAC 化疗反应的影响，特别关注紫杉醇。使用 Alamar Blue 测定法评估 EAC 细胞系 OE19、FLO-1、OE33 和 SK-GT-4 对紫杉醇的反应。通过免疫印迹法检测 LC3B-II 和定量评估 WIP1 mRNA 评估紫杉醇处理体外自噬通量。对接受新辅助化疗的 149 例 EAC 患者的肿瘤组织进行自噬标志物 LC3B 和 p62 的免疫组化染色，包括治疗前和治疗后样本（62 对匹配）。通过组织学评估肿瘤反应。为了进行比较，还使用了之前发表的 114 例原发性 EAC 病例的数据。EAC 细胞系对紫杉醇治疗的反应不同；然而，这与自噬调节的差异无关。单独高 p62 细胞质表达（p ≤ 0.001），或与低 LC3B 联合（p = 0.034），与化疗无反应相关，无论方案是否包含紫杉醇，但在新辅助治疗后，LC3B 或 p62 表达模式对 EAC 没有独立的预后价值。p62 和相关途径，很可能不是自噬，在临床环境中在 EAC 的化疗反应中发挥作用。因此，p62 可能是克服 EAC 化疗耐药性的新治疗靶点。
