title: Glucose deprivation induces G2/M transition-arrest and cell death in N-GlcNAc2-modified protein-producing renal carcinoma cells.
abstract: Some cancer cells can survive under glucose deprivation within the microenvironment of a tumor. Recently, we reported that N-linked (β-N-acetylglucosamine)2 [N-GlcNAc2]-modified proteins induce G2/M arrest and cell death under glucose deprivation. Here, we investigated whether such a response to glucose deprivation contributes to the survival of renal cell carcinomas, which are sensitive to nutritional stress. Specifically, we analyzed seven renal carcinoma cell lines. Four of these cell lines produced N-GlcNAc2-modified proteins and led G2/M-phase arrest under glucose deprivation, leading to cell death. The remaining three cell lines did not produce N-GlcNAc2-modified proteins and undergo G1/S-phase arrest under glucose deprivation, leading to survival. The four dead cell lines displayed significant up-regulation in the UDP-GlcNAc biosynthesis pathway as well as increased phosphorylation of p53, which was not observed in the surviving three cell lines. In addition, the four dead cell lines showed prolonged up-regulated expression of ATF3, which is related to unfolded protein response (UPR), while the surviving three cell lines showed only transient up-regulation of ATF3. In this study, we demonstrated that the renal carcinoma cells which accumulate N-GlcNAc2-modified proteins under glucose deprivation do not survive with abnormaly prolonged UPR pathway. By contrast, renal carcinoma cells that do not accumulate N-GlcNAc2-modified proteins under these conditions survive. Morover, we demonstrated that buformin, a UPR inhibitor, efficiently reduced cell survival under conditions of glucose deprivation for both sensitive and resistant phenotypes. Further studies to clarify these findings will lead to the development of novel chemotherapeutic treatments for renal cancer.
authors.affiliation: Central Reseach Laboratory, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Isono
authors.affiliation: Departments of Clinical Laboratory Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Chano
authors.affiliation: Central Reseach Laboratory, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Kitamura
authors.affiliation: Departments of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D051700:Activating Transcription Factor 3 / Q000096:biosynthesis; D002026:Buformin / Q000494:pharmacology; D016923:Cell Death; D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose; D006023:Glycoproteins / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007680:Kidney Neoplasms; D059566:M Phase Cell Cycle Checkpoints; D059016:Tumor Microenvironment; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D006023:Glycoproteins; D007004:Hypoglycemic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005947:Glucose; D000117:Acetylglucosamine; D002026:Buformin