Phosphoinositide 3-kinase accelerates postoperative tumor growth by inhibiting apoptosis and enhancing resistance to chemotherapy-induced apoptosis. Novel role for an old enemy.
Coffey, J Calvin Wang, Jiang Huai Smith, Myles J F Laing, Alan Bouchier-Hayes, David Cotter, Tom G Redmond, H Paul
Coffey, J Calvin
Wang, Jiang Huai
Smith, Myles J F
Laing, Alan
Bouchier-Hayes, David
Cotter, Tom G
Redmond, H Paul
Advisors
Editors
Other Contributors
Date
2012-02-03T15:07:25Z
Date Submitted
Keywords
Other Subjects
Subject 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
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
Planned Date
Start Date
Collaborators
Principal Investigators
Alternative Titles
Publisher
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
ISSN
0021-9258 (Print)
0021-9258 (Linking)
0021-9258 (Linking)
eISSN
ISBN
DOI
10.1074/jbc.M414696200
PMID
15741161