Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing, 100071, China.
School of Public Health, Sichuan University, Chengdu, 610041, China.
Gastric Cancer. 2022 Jan;25(1):96-106. doi: 10.1007/s10120-021-01229-x. Epub 2021 Aug 9.
The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.
PTEN 基因是 PI3K/Akt/mTOR 通路中的肿瘤抑制基因，对于抑制肿瘤生长和转移至关重要。然而，PTEN 基因突变是否会引起肿瘤发生以及影响胃癌的治疗效果仍不清楚。本研究旨在通过干扰 Akt/mTOR 通路，探讨雷帕霉素（Rapamycin）和氟尿嘧啶（5-Fu）联合应用对 PTEN 条件性缺失小鼠模型胃肿瘤发生的治疗作用。三组小鼠分别连续 5 天接受 Rapamycin、5-Fu 以及两者联合处理，分析 Akt/mTOR 通路基因表达、caspase-3 和 p-Akt、p-S6K、p-4EBP1 蛋白表达以及胃组织病理学变化。本研究结果表明，胃腺细胞中条件性缺失 PTEN 会诱导小鼠发生增生性胃肿瘤。与单独使用 Rapamycin 或 5-Fu 相比，联合应用 Rapamycin 和 5-Fu 可通过抑制 mTOR 信号通路，对胃癌治疗具有更好的效果。本研究表明，雷帕霉素与化疗药物 5-Fu 具有协同作用，为治疗 Akt/mTOR 通路异常激活的胃腺肿瘤提供了一种潜在的联合治疗策略，为胃癌的临床治疗中抑制 Akt/mTOR 通路提供了重要的见解。
