title: GSH-dependent antioxidant defense contributes to the acclimation of colon cancer cells to acidic microenvironment.
abstract: Due to increased glycolysis and poor local perfusion, solid tumors are usually immersed in an acidic microenvironment. While extracellular acidosis is cytotoxic, cancer cells eventually become acclimated to it. While previous studies have addressed the acute effect of acidosis on cancer cells, little is known about how cancer cells survive chronic acidosis. In this study we exposed colorectal cancer (CRC) cells (HCT15, HCT116 and LoVo) to acidic pH (pH 6.5) continuously for over three months and obtained CRC cells that become acclimated to acidic pH, designated as CRC-acidosis-acclimated or CRC-AA. We unexpectedly found that while acute exposure to low pH resulted in an increase in the level of intracellular reactive oxygen species (ROS), CRC-AA cells exhibited a significantly reduced level of ROS when compared to ancestor cells. CRC-AA cells were found to maintain a higher level of reduced glutathione, via the upregulation of CD44 and glutathione reductase (GSR), among others, than their ancestor cells. Importantly, CRC-AA cells were more sensitive to agents that deplete GSH. Moreover, downregulation of GSR by RNA interference was more deleterious to CRC-AA cells than to control cells. Together, our results demonstrate a critical role of glutathione-dependent antioxidant defense in acclimation of CRC cells to acidic extracellular pH.
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Minnan
authors.initials: M
authors.lastname: Zhao
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Liu
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Yanchao
authors.initials: Y
authors.lastname: Gong
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Xu
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Liu
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Caibo
authors.initials: C
authors.lastname: Zhang
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Guo
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Xiyu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
authors.affiliation: a Ministry of Education Key Laboratory of Experimental Teratology and Department of Molecular Medicine and Genetics, Shandong University School of Medicine , Jinan , China.|b Department of Genetics/Human Genetics Institute of New Jersey , Rutgers University , Piscataway , NJ , USA.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
mesh_terms: D000138:Acidosis / Q000473:pathology; D000143:Acids / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism*; D005980:Glutathione Reductase / Q000378:metabolism; D006801:Humans; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000143:Acids; D000975:Antioxidants; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D005980:Glutathione Reductase; D005978:Glutathione
keywords: CD44; GSH; GSR; acidic microenvironment; antioxidant defense; colorectal cancer