Upregulation of ABCG2 via the PI3K-Akt pathway contributes to acidic microenvironment-induced cisplatin resistance in A549 and LTEP-a-2 lung cancer cells

被引:19
|
作者
Hu, Chun Fang [1 ]
Huang, Yi Ying [1 ]
Wang, Yong Jie [1 ]
Gao, Feng Guang [1 ,2 ]
机构
[1] Xiamen Univ, Coll Med, Basic Med Sci, Dept Immunol, Xiamen 361102, Fujian, Peoples R China
[2] Shang Hai Jiao Tong Univ, State Key Lab Oncogenes & Related Genes, Shanghai 200032, Peoples R China
基金
中国国家自然科学基金;
关键词
acidification; tumor environment; multidrug resistance; lung cancer; ABCG2; PI3K; Akt; KAPPA-B PATHWAY; STEM-LIKE CELLS; MULTIDRUG-RESISTANCE; OVARIAN-CANCER; DNA-PK; INTERLEUKIN-6; EXPRESSION; IL-6; ACTIVATION; PACLITAXEL;
D O I
10.3892/or.2016.4827
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Hypoxia always exists in the processes involved in the development of lung cancer and contributes to an acidic microenvironment. Despite that hypoxia in the tumor microenvironment is associated with the formation of chemotherapeutic resistance, the exact role of an acidic microenvironment in the development of hypoxia-induced lung cancer multidrug resistance is still unknown. In the present study, we acidized the medium with 2-(N-morpholino)-ethanesulfonic acid (MES monohydrate) to mimic the acidic tumor microenvironment and observed the effects of acidification on lung cancer cell viability, the expression of ATP-binding cassette sub-family G member 2 (ABCG2) and myeloid cell leukemia-1 (Mcl-1), and activation of the PI3K-Akt pathway. Thereafter, we investigated the mechanisms involved in the acidification-induced expression of ABCG2 and Mcl-1, and the potential therapeutic strategy to overcome acidification-associated multidrug resistance formation. We demonstrated that acidification obviously increased the expression of ABCG2 and Mcl-1 via PI3K-Akt-mTOR-S6 pathway activation and contributed to multidrug resistance. Inhibition of PI3K-Akt activity efficiently abolished the effect of acidification on cell viability, indicating that the PI3K-Akt pathway may include potential therapeutic target molecules in acidized microenvironment-associated lung cancer chemotherapeutic resistance.
引用
收藏
页码:455 / 461
页数:7
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