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Phosphoinositide 3-Kinase Accelerates Postoperative Tumor Growth by Inhibiting Apoptosis and Enhancing Resistance to Chemotherapy-induced Apoptosis

J. Biol. Chem., 3 June 2005
Vol. 280, Issue 22, p. 20968-20977
DOI: 10.1074/jbc.M414696200

Phosphoinositide 3-Kinase Accelerates Postoperative Tumor Growth by Inhibiting Apoptosis and Enhancing Resistance to Chemotherapy-induced Apoptosis

NOVEL ROLE FOR AN OLD ENEMY*

  1. J. Calvin Coffey§,
  2. Jiang Huai Wang,
  3. Myles J. F. Smith,
  4. Alan Laing,
  5. David Bouchier-Hayes,
  6. Tom G. Cotter** and
  7. H. Paul Redmond
  1. Departments of Surgery, Tumor Biology, and **Biochemistry, Cork University Hospital, Wilton, Cork, Munster, Ireland and the Department Surgery, Beaumont Hospital and Royal College of Surgeons, Dublin, Ireland
  1. § To whom correspondence should be addressed: Tel.: 35-386-838-2421; Fax: 35-321-492-2811; E-mail: calvincoffey{at}hotmail.com.

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 p110γ and p85α 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.

Footnotes

  • 1 The abbreviations used are: TRAIL, tumor necrosis factor apoptosis-inducing ligand; RT, recurrent tumor; H&E, hematoxylin and eosin; MSDr, mean signal density or fold difference; PI3K, phosphatidylinositol 3-kinase; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.

  • * This work was supported by research grants from the Health Research Board Ireland and also from Aid Cancer Treatment. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Embedded Image The on-line version of this article (available at http://www.jbc.org) contains additional text.

    • Received December 30, 2004.
    • Revision received February 15, 2005.

Citation:

J. C. Coffey, J. H. Wang, M. J. Smith, A. Laing, D. Bouchier-Hayes, T. G. Cotter, and H. P. Redmond, Phosphoinositide 3-Kinase Accelerates Postoperative Tumor Growth by Inhibiting Apoptosis and Enhancing Resistance to Chemotherapy-induced Apoptosis. J. Biol. Chem. 280, 20968-20977 (2005).

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