Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy.

Hdl Handle:
http://hdl.handle.net/10147/208919
Title:
Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy.
Authors:
Coffey, J Calvin; Wang, Jiang Huai; Smith, Myles J F; Laing, Alan; Bouchier-Hayes, David; Cotter, Tom G; Redmond, H Paul
Affiliation:
Department of Surgery, Cork University Hospital, Wilton, Cork, Munster, Ireland. , calvincoffey@hotmail.com
Citation:
J Biol Chem. 2005 Jun 3;280(22):20968-77. Epub 2005 Mar 1.
Journal:
The Journal of biological chemistry
Issue Date:
3-Feb-2012
URI:
http://hdl.handle.net/10147/208919
DOI:
10.1074/jbc.M414696200
PubMed ID:
15741161
Abstract:
Tumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.
Language:
eng
MeSH:
Animals; Antineoplastic Agents/*pharmacology; *Apoptosis; Apoptosis Regulatory Proteins; Blotting, Western; Cell Line; Chromones/pharmacology; Computational Biology; *Drug Resistance, Neoplasm; Enzyme Inhibitors/pharmacology; Epithelium/metabolism; *Gene Expression Regulation, Neoplastic; Humans; In Situ Nick-End Labeling; Membrane Glycoproteins/metabolism; Mice; Mice, Nude; Mice, SCID; Morpholines/pharmacology; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms/*pathology; Oligonucleotide Array Sequence Analysis; Oligonucleotides/chemistry; Phenotype; Phosphatidylinositol 3-Kinases/metabolism/*physiology; Propidium/pharmacology; RNA/chemistry; Recurrence; TNF-Related Apoptosis-Inducing Ligand; Time Factors; Tumor Necrosis Factor-alpha/metabolism
ISSN:
0021-9258 (Print); 0021-9258 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorCoffey, J Calvinen_GB
dc.contributor.authorWang, Jiang Huaien_GB
dc.contributor.authorSmith, Myles J Fen_GB
dc.contributor.authorLaing, Alanen_GB
dc.contributor.authorBouchier-Hayes, Daviden_GB
dc.contributor.authorCotter, Tom Gen_GB
dc.contributor.authorRedmond, H Paulen_GB
dc.date.accessioned2012-02-03T15:07:25Z-
dc.date.available2012-02-03T15:07:25Z-
dc.date.issued2012-02-03T15:07:25Z-
dc.identifier.citationJ Biol Chem. 2005 Jun 3;280(22):20968-77. Epub 2005 Mar 1.en_GB
dc.identifier.issn0021-9258 (Print)en_GB
dc.identifier.issn0021-9258 (Linking)en_GB
dc.identifier.pmid15741161en_GB
dc.identifier.doi10.1074/jbc.M414696200en_GB
dc.identifier.urihttp://hdl.handle.net/10147/208919-
dc.description.abstractTumor removal remains the principal treatment modality in the management of solid tumors. The process of tumor removal may potentiate the resurgent growth of residual neoplastic tissue. Herein, we describe a novel murine model in which flank tumor cytoreduction is followed by accelerated local tumor recurrence. This model held for primary and recurrent tumors generated using a panel of human and murine (LS174T, DU145, SW480, SW640, and 3LL) cell lines and replicated accelerated tumor growth following excisional surgery. In investigating this further, epithelial cells were purified from LS174T primary and corresponding recurrent tumors for comparison. Baseline as well as tumor necrosis factor apoptosis-inducing ligand (TRAIL)-induced apoptosis were significantly reduced in recurrent tumor epithelia. Primary and recurrent tumor gene expression profiles were then compared. This identified an increase and reduction in the expression of p110gamma and p85alpha class Ia phosphoinositide 3-kinase (PI3K) subunits in recurrent tumor epithelia. These changes were further confirmed at the protein level. The targeting of PI3K ex vivo, using LY294002, restored sensitivity to TRAIL in recurrent tumor epithelia. In vivo, adjuvant LY294002 prolonged survival and significantly attenuated recurrent tumor growth by greatly enhancing apoptosis levels. Hence, PI3K plays a role in generating the antiapoptotic and chemoresistant phenotype associated with accelerated local tumor recurrence.en_GB
dc.language.isoengen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshAntineoplastic Agents/*pharmacologyen_GB
dc.subject.mesh*Apoptosisen_GB
dc.subject.meshApoptosis Regulatory Proteinsen_GB
dc.subject.meshBlotting, Westernen_GB
dc.subject.meshCell Lineen_GB
dc.subject.meshChromones/pharmacologyen_GB
dc.subject.meshComputational Biologyen_GB
dc.subject.mesh*Drug Resistance, Neoplasmen_GB
dc.subject.meshEnzyme Inhibitors/pharmacologyen_GB
dc.subject.meshEpithelium/metabolismen_GB
dc.subject.mesh*Gene Expression Regulation, Neoplasticen_GB
dc.subject.meshHumansen_GB
dc.subject.meshIn Situ Nick-End Labelingen_GB
dc.subject.meshMembrane Glycoproteins/metabolismen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMice, Nudeen_GB
dc.subject.meshMice, SCIDen_GB
dc.subject.meshMorpholines/pharmacologyen_GB
dc.subject.meshNeoplasm Metastasisen_GB
dc.subject.meshNeoplasm Transplantationen_GB
dc.subject.meshNeoplasms/*pathologyen_GB
dc.subject.meshOligonucleotide Array Sequence Analysisen_GB
dc.subject.meshOligonucleotides/chemistryen_GB
dc.subject.meshPhenotypeen_GB
dc.subject.meshPhosphatidylinositol 3-Kinases/metabolism/*physiologyen_GB
dc.subject.meshPropidium/pharmacologyen_GB
dc.subject.meshRNA/chemistryen_GB
dc.subject.meshRecurrenceen_GB
dc.subject.meshTNF-Related Apoptosis-Inducing Liganden_GB
dc.subject.meshTime Factorsen_GB
dc.subject.meshTumor Necrosis Factor-alpha/metabolismen_GB
dc.titlePhosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy.en_GB
dc.contributor.departmentDepartment of Surgery, Cork University Hospital, Wilton, Cork, Munster, Ireland. , calvincoffey@hotmail.comen_GB
dc.identifier.journalThe Journal of biological chemistryen_GB
dc.description.provinceMunster-

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