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MUC1-C 的抑制通过 AKT 通路调节食管鳞癌细胞代谢。

Inhibition of MUC1-C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma.

机构信息

Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.

Department of Thoracic Surgery, Laiwu City People's Hospital, Laiwu, Shandong, China.

出版信息

J Cell Physiol. 2019 Jul;234(7):12019-12028. doi: 10.1002/jcp.27863. Epub 2018 Dec 6.

DOI:10.1002/jcp.27863
PMID:30523643
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6587484/
Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common digestive tumors worldwide. The Mucin 1 (MUC1) heterodimeric protein has been confirmed that is overexpressed in ESCC and induced adverse outcomes. However, the detailed mechanism(s) remained challenging. So, we investigated the relationship between MUC1-C and metabolism in ESCC cells. In the results, TP53-induced glycolysis and apoptosis regulator (TIGAR) was overexpressed and correlative with MUC1-C positively in ESCC tissue. Targeting MUC1-C inhibits AKT-mTORC-S6K1 signaling and blocks TIGAR translation. We found that the inhibitory effect of GO-203 on TIGAR was mediated by inhibition of AKT-mTOR-S6K1 pathway. The findings also demonstrated that the suppressive effect of GO-203 on TIGAR is related to the decrease of glutathione level, the increase of reactive oxygen species and the loss of mitochondrial transmembrane membrane potential. In xenograft tissues, GO-203 inhibited the growth of ESCC cells and lead to the low expression of transmembrane C-terminal subunit (MUC1-C) and TIGAR. This evidence supports the contention that MUC1-C is significant for metabolism in ESCC and indicated that MUC1-C is a potential target for the treatment of ESCC.

摘要

食管鳞状细胞癌（ESCC）是全球最常见的消化系统肿瘤之一。Mucin 1（MUC1）异二聚体蛋白已被证实在 ESCC 中过度表达，并诱导不良结局。然而，其详细的机制仍然具有挑战性。因此，我们研究了 MUC1-C 与 ESCC 细胞代谢之间的关系。结果表明，TP53 诱导的糖酵解和凋亡调节因子（TIGAR）在 ESCC 组织中过度表达，并与 MUC1-C 呈正相关。靶向 MUC1-C 可抑制 AKT-mTORC-S6K1 信号通路并阻断 TIGAR 翻译。我们发现 GO-203 对 TIGAR 的抑制作用是通过抑制 AKT-mTOR-S6K1 通路介导的。研究结果还表明，GO-203 对 TIGAR 的抑制作用与谷胱甘肽水平降低、活性氧增加和线粒体跨膜膜电位丧失有关。在异种移植组织中，GO-203 抑制 ESCC 细胞的生长，并导致跨膜 C 端亚基（MUC1-C）和 TIGAR 的低表达。这一证据支持了 MUC1-C 对 ESCC 代谢具有重要意义的观点，并表明 MUC1-C 是治疗 ESCC 的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/de3cb7dacd5c/JCP-234-12019-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/bca011aa6a95/JCP-234-12019-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/9a96ad5f9d2e/JCP-234-12019-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/2da710bcecc6/JCP-234-12019-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/c878755b9abf/JCP-234-12019-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/35053e34bad7/JCP-234-12019-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/de3cb7dacd5c/JCP-234-12019-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/bca011aa6a95/JCP-234-12019-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/9a96ad5f9d2e/JCP-234-12019-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/2da710bcecc6/JCP-234-12019-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/c878755b9abf/JCP-234-12019-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/35053e34bad7/JCP-234-12019-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c8fc/6587484/de3cb7dacd5c/JCP-234-12019-g006.jpg

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