title: Upregulation of ABCG2 via the PI3K-Akt pathway contributes to acidic microenvironment-induced cisplatin resistance in A549 and LTEP-a-2 lung cancer cells.
abstract: 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.
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
authors.forename: Chun Fang
authors.initials: CF
authors.lastname: Hu
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
authors.forename: Yi Ying
authors.initials: YY
authors.lastname: Huang
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
authors.forename: Yong Jie
authors.initials: YJ
authors.lastname: Wang
authors.affiliation: Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China.
authors.forename: Feng Guang
authors.initials: FG
authors.lastname: Gao
mesh_terms: D000072283:A549 Cells; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D002945:Cisplatin; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C116614:ABCG2 protein, human; C579095:MCL1 protein, human; C546842:MTOR protein, human