title: Loss of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) induces apoptotic processes in pancreatic carcinoma cells.
abstract: Early invasive growth and metastasis are features of pancreatic cancer that rely on its resistance to anoikis, an apoptosis program activated on loss of matrix anchorage. How anoikis is regulated is unclear. UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine-kinase (GNE) was silenced, or p16 was overexpressed, in human pancreatic carcinoma cells. Gene expression profiling, enzymatic assays, Western blotting, and cell cycle analysis were conducted. Silencing of GNE, the key enzyme of sialic acid biosynthesis, sensitizes pancreatic cancer cells to anoikis. Accordingly, we observed a loss of GNE enzyme activity in cells, which became anoikis susceptible after transfection with the tumor suppressor p16. Similarly, studies of another cell line with low GNE activity revealed strong anoikis susceptibility, confirming the association of low GNE activity and anoikis susceptibility. Gene expression profiling demonstrated that the loss of GNE triggered the transcriptional activation of the ATF4-ATF3-CHOP pathway, leading to apoptosis in the framework of the unfolded protein response. In silico analysis showed that GNE up-regulation occurred predominantly in pancreatic cancer but also in other malignancies. Delineation of GNE-dependent signaling pathways may provide targets that control anchorage dependence and/or restore drug efficacy, which is of utmost relevance for the treatment of pancreatic cancer.
authors: Research Group Surgical Oncology, Experimental and Clinical Research Center, Charité Campus Buch, Berlin, Germany. wkemmner@mdc-berlin.de
authors: Wolfgang
authors: W
authors: Kemmner
authors: Pia
authors: P
authors: Kessel
authors: Hugo
authors: H
authors: Sanchez-Ruderisch
authors: Heinz
authors: H
authors: Möller
authors: Stephan
authors: S
authors: Hinderlich
authors: Peter M
authors: PM
authors: Schlag
authors: Katharina
authors: K
authors: Detjen
mesh_terms: D023102:Anoikis / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D055785:Gene Knockdown Techniques; D019942:Genes, p16; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012794:Sialic Acids / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D039081:Integrin alpha5beta1; D009097:Multienzyme Complexes; D034741:RNA, Small Interfering; D012794:Sialic Acids; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase