title: ZIP4 confers resistance to zinc deficiency-induced apoptosis in pancreatic cancer.
abstract: Emerging evidence implicates the zinc importer ZIP4 as a critical factor that enhances pancreatic cancer proliferation; however, the role of ZIP4 in promoting pancreatic cancer progression by regulating apoptosis requires elucidation. To determine the effect of ZIP4 on apoptosis, we used cell lines where ZIP4 levels were upregulated or silenced in combination with Chelex 100 treatment to deplete intracellular zinc. Pancreatic cancer xenografts derived from those cells were also included. TUNEL and flow cytometry analysis were used to measure apoptosis and western blotting was used to analyze protein expression for PARP and multiple caspases. Cell cycle profiles were examined by flow cytometry. Zinc depletion by Chelex induced more apoptosis of pancreatic cancer cells in comparison to normal medium, where almost no apoptosis was observed. ZIP4 stably overexpressed MIA PaCa-2 (MIA-ZIP4) cells were more resistant to zinc depletion-induced apoptosis compared with vector control. Conversely, AsPC-1 (AsPC-shZIP4) cells with stable knockdown of ZIP4 were more sensitive to zinc deficiency than control. Resistance to apoptosis mediated by ZIP4 was accomplished by the caspase pathway. In vivo data also confirmed that ZIP4 overexpressed xenografts showed less apoptosis than controls. Cell cycle profiles indicate that silencing of ZIP4 leads to decreased cell population in S phase and G 0/G 1 arrest. These results described a previously uncharacterized role of ZIP4 in apoptosis resistance and elucidated a novel pathway through which ZIP4 regulates pancreatic cancer growth. This research provides additional evidence for ZIP4 and related signaling cascade as a molecular target for therapeutic intervention in pancreatic cancer.
authors.affiliation: The Vivian L. Smith Department of Neurosurgery; University of Texas Medical School at Houston; Houston, TX USA.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Cancer Biology; University of Texas MD Anderson Cancer Center; Houston, TX USA.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Vivian L. Smith Department of Neurosurgery; University of Texas Medical School at Houston; Houston, TX USA.
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Yang
authors.affiliation: The Vivian L. Smith Department of Neurosurgery; University of Texas Medical School at Houston; Houston, TX USA; Department of Gastroenterology; Changhai Hospital; Second Military Medical University; Shanghai, China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Sun
authors.affiliation: The Vivian L. Smith Department of Neurosurgery; University of Texas Medical School at Houston; Houston, TX USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Hagan
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition; University of Texas Medical School at Houston; Houston, TX USA.
authors.forename: Sushovan
authors.initials: S
authors.lastname: Guha
authors.affiliation: The Vivian L. Smith Department of Neurosurgery; University of Texas Medical School at Houston; Houston, TX USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C486791:SLC39A4 protein, human; D020169:Caspases; D015032:Zinc
keywords: ZIP4; apoptosis; caspase; cell cycle; pancreatic cancer