The TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop increases the cisplatin resistance of non-small cell lung cancer by inducing G6PD expression

被引:10
作者
Zhang, Rongwei [1 ,3 ]
Tao, Fuzheng [2 ]
Ruan, Shenghui [3 ]
Hu, Miaoxian [3 ]
Hu, Yanyan [4 ]
Fang, Zejun [4 ]
Mei, Lingming [5 ]
Gong, Chaoju [6 ]
机构
[1] Chinese & Western Combined Hosp Taizhou, Div Thorac Surg, Wenlin 317523, Peoples R China
[2] Chinese & Western Combined Hosp Taizhou, Dept Cardiovasc, Wenlin 317523, Peoples R China
[3] Chinese & Western Combined Hosp Taizhou, Dept Emergency, Wenlin 317523, Peoples R China
[4] Sanmen Peoples Hosp Zhejiang, Cent Lab, Sanmen 317100, Peoples R China
[5] Sanmen Peoples Hosp Zhejiang, Dept Educ, 171 Renmin Rd, Sanmen 317100, Peoples R China
[6] Xuzhou Med Univ, Cent Lab, Municipal Affiliated Hosp, Xuzhou 221002, Jiangsu, Peoples R China
来源
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH | 2019年 / 11卷 / 11期
关键词
Non-small-cell lung cancer (NSCLC); transforming growth factor beta 1 (TGF beta 1); forkhead box protein M1 (FOXM1); high-mobility group Al (HMGA1); glucose-6-phosphate dehydrogenase (G6PD); cisplatin resistance; TGF-BETA PATHWAY; BREAST-CANCER; GEMCITABINE RESISTANCE; HMGA1; EXPRESSION; A549; CELLS; FOXM1; INVOLVEMENT; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; ADENOCARCINOMA; CONTRIBUTES;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Platinum-based chemotherapy is still widely applied for the treatment of advanced non-small cell lung cancer (NSCLC). However, acquired chemoresistance compromises the curative effect of this drug. In this study, we found that glucose-6-phosphate dehydrogenase (G6PD), a critical enzyme of the pentose phosphate pathway, contributed to cisplatin resistance in NSCLC. The experimental results showed that transforming growth factor beta 1 (TGF beta 1) increased the expression of G6PD by activating the forkhead box protein M1-high mobility group AT-hook 1-G6PD (FOXM1-HMGA1-G6PD) transcriptional regulatory pathway, in which TGF beta 1 inhibited the ubiquitination and degradation of FOXM1 protein. Additionally, HMGA1 induced TGF beta 1 expression, and neutralized TGF beta 1 in the culture medium downregulated HMGA1 levels, suggesting the existence of a TGF beta 1-FOXM1-HMGA1-TGF beta 1 positive feedback loop and its role in maintaining G6PD expression. Further investigations showed that exogenous TGF beta 1 enhanced the cisplatin resistance of NSCLC cells, while disrupting the FOXM1-HMGAl-G6PD pathway, thereby sensitizing the cells to cisplatin. Consistently, the TGF beta 1-FOXM1-HMGA1-G6PD axis was confirmed in NSCLC tissues, and overactivation of this axis predicted poor survival in NSCLC patients. Collectively, the results of this study demonstrate that the TGF beta 1-FOXM1-HMGA1-TGF beta 1 positive feedback loop plays a crucial role in the cisplatin resistance of NSCLC by upregulating the expression of G6PD, providing a potential therapeutic target to restore chemosensitivity in cisplatin-resistant NSCLC.
引用
收藏
页码:6860 / 6876
页数:17
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