title: Inhibition of oncogenic Pim-3 kinase modulates transformed growth and chemosensitizes pancreatic cancer cells to gemcitabine.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a 5-year survival rate of only 6%. Although the cytosine analog gemcitabine is the drug commonly used to treat PDAC, chemoresistance unfortunately renders the drug ineffective. Thus, strategies that can decrease this resistance will be essential for improving the dismal outcome of patients suffering from this disease. We previously observed that oncogenic Pim-1 kinase was aberrantly expressed in PDAC tissues and cell lines and was responsible for radioresistance. Furthermore, members of the Pim family have been shown to reduce the efficacy of chemotherapeutic drugs in cancer. Therefore, we attempted to evaluate the role of Pim-3 in chemoresistance of PDAC cells. We were able to confirm upregulation of the Pim-3 oncogene in PDAC tissues and cell lines versus normal samples. Biological consequences of inhibiting Pim-3 expression with shRNA-mediated suppression included decreases in anchorage-dependent growth, invasion through Matrigel and chemoresistance to gemcitabine as measured by caspase-3 activity. Additionally, we were able to demonstrate that Pim-1 and Pim-3 play overlapping but non-identical roles as it relates to gemcitabine sensitivity of pancreatic cancer cells. To further support the role of Pim-3 suppression in sensitizing PDAC cells to gemcitabine, we used the pharmacological Pim kinase inhibitor SGI-1776. Treatment of PDAC cells with SGI-1776 resulted in decreased phosphorylation of the proapoptotic protein Bad and cell cycle changes. When SGI-1776 was combined with gemcitabine, there was a greater decrease in cell viability in the PDAC cells versus cells treated with either of the drugs separately. These results suggest combining drug therapies that inhibit Pim kinases, such as Pim-3, with chemotherapeutic agents, to aid in decreasing chemoresistance in pancreatic cancer.
authors.affiliation: State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Xu
authors.forename: Michael G
authors.initials: MG
authors.lastname: Cobb
authors.forename: Lily
authors.initials: L
authors.lastname: Gavilano
authors.forename: Sam M
authors.initials: SM
authors.lastname: Witherspoon
authors.forename: Daniel
authors.initials: D
authors.lastname: Williams
authors.forename: Catherine D
authors.initials: CD
authors.lastname: White
authors.forename: Pietro
authors.initials: P
authors.lastname: Taverna
authors.forename: Brian K
authors.initials: BK
authors.lastname: Bednarski
authors.forename: Hong Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Antonio T
authors.initials: AT
authors.lastname: Baines
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D034741:RNA, Small Interfering; D051025:bcl-Associated Death Protein / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C494819:BAD protein, human; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D011724:Pyridazines; D034741:RNA, Small Interfering; C545188:SGI 1776; D051025:bcl-Associated Death Protein; D003841:Deoxycytidine; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D000093542:Gemcitabine
keywords: Pim kinase; Pim-3 kinase; chemoresistance; chemosensitivity; gemcitabine; pancreatic cancer; transformed growth