蛋白激酶B
癌症研究
细胞生长
基因敲除
紫杉醇
细胞凋亡
三阴性乳腺癌
细胞周期
癌基因
活力测定
葛兰素史克-3
PI3K/AKT/mTOR通路
化学
生物
乳腺癌
信号转导
医学
癌症
内科学
生物化学
作者
Yan Chang,Huiqin Jia,Bin Xu,Yang Liu,Yetong Xu,Jingyu Zhang,Mei‐Qi Wang,Lixian Yang,Zhao-Hui Song
摘要
Abstract Triple‐negative breast cancer (TNBC) has an aggressive clinical course, and paclitaxel (PTX)‐based chemotherapy remains the main therapeutic drug. Metadherin (MTDH) acts as an oncogene that regulates proliferation, invasion, metastasis, and chemoresistance. This study aimed to investigate whether TNBC chemosensitivity to PTX was related to the MTDH/AKT/glycogen synthase kinase‐3beta (GSK‐3β) pathway. Clinical baseline characteristics and immunohistochemistry (IHC) were used to evaluate the expression and prognosis of MTDH and AKT (protein kinase B, PKB) in TNBC patient samples. MTDH shRNA, MTDH overexpression vector, MK‐2206, and PTX intervention were used in cell models and mouse tumor‐bearing models. Afterwards, mRNA and protein levels were assessed using quantitative real‐time polymerase chain reaction and Western blot. Evaluate the level of tumor cell apoptosis and cell cycle using flow cytometry. Cell viability was detected using Cell Count Kit 8. The in vivo imaging system is used to analyze the growth of tumors. We found that higher expression of MTDH or AKT resulted in poorer disease‐free survival and a lower Miller–Payne grade. MTDH promotes cell proliferation and increases p‐AKT and p‐GSK‐3β expression in TNBC cells. Notably, suppression of AKT terminated MTDH overexpression‐induced cell proliferation and apoptosis. MTDH knockdown or the AKT inhibitor MK2206 reduced the p‐AKT and p‐GSK‐3β ratio, reduced cell viability and proliferation, increased cell apoptosis, and increased chemosensitivity to PTX. In vivo, xenograft tumors of an MTDH knockdown+MK2206 group treated with PTX were the smallest compared to other groups. In short, MTDH inhibits TNBC chemosensitivity to PTX by activating the AKT/GSK‐3β signaling pathway.
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