Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
Biomolecules. 2024 Sep 4;14(9):1115. doi: 10.3390/biom14091115.
Esophageal adenocarcinoma (EAC) is a subtype of esophageal cancer that is difficult to treat, with overall poor survival and frequent recurrence despite curative-intent treatment strategies. There is limited understanding of EAC resistance mechanisms to chemotherapy or radiation. We have found that the AMP-activated protein kinase (AMPK) can serve a pro-survival function in EAC cells in response to cytotoxic treatments. Treatment with the IL-6 inhibitor tocilizumab, which previously has been shown to inhibit EAC organoid growth, resulted in the activation of AMPK in the OE33 EAC cell line, which was accompanied by a decrease in MTORC1 signaling and an increase in oxidative mitochondrial metabolism, both known downstream effects of AMPK activation to promote cell survival under conditions of metabolic stress. This increase in oxidative metabolism was abrogated in cells with a genetic knockdown of AMPK expression. Furthermore, we found that AMPK was activated in OE33 cells following treatment with cisplatin or ionizing radiation. Treatment with the AMPK inhibitor Compound C or genetic knockdown of AMPK expression enhanced cell death in a synergistic manner with chemotherapeutics or ionizing radiation. These findings were recapitulated in human patient-derived EAC organoids, suggesting that AMPK may be a common pro-survival mechanism to confer treatment resistance in EAC and may serve as a novel target to enhance the efficacy of current and future treatment strategies.
食管腺癌（EAC）是一种难以治疗的食管癌亚型，尽管采用了以治愈为目的的治疗策略，但总体生存率仍然较低，且经常复发。对于 EAC 对化疗或放疗的耐药机制，目前的了解还很有限。我们发现，在细胞毒性治疗中，AMP 激活的蛋白激酶（AMPK）可以在 EAC 细胞中发挥生存促进作用。先前的研究表明，白细胞介素 6（IL-6）抑制剂托珠单抗可以抑制 EAC 类器官的生长，在 OE33 EAC 细胞系中，这种抑制剂的作用会导致 AMPK 的激活，同时伴随着 MTORC1 信号的降低和氧化线粒体代谢的增加，这两者都是 AMPK 激活以促进代谢应激下细胞存活的已知下游效应。AMPK 表达的基因敲低会削弱这种氧化代谢的增加。此外，我们发现顺铂或电离辐射处理后 OE33 细胞中 AMPK 被激活。用 AMPK 抑制剂 Compound C 或 AMPK 表达的基因敲低以协同方式增强与化疗药物或电离辐射的细胞死亡。这些发现也在人源性 EAC 类器官中得到了重现，表明 AMPK 可能是一种常见的生存促进机制，赋予 EAC 治疗耐药性，并且可以作为增强现有和未来治疗策略疗效的新靶点。
