title: Targeting the phosphatidylinositol 3-kinase/Akt pathway for enhancing breast cancer cells to radiotherapy.
abstract: The phosphatidylinositol 3-kinase (PI-3K)/Akt pathway, regulated by its upstream growth factor receptor tyrosine kinases, plays a critical role in promoting cell proliferation and inhibiting cell death. The aim of this study was to determine whether the PI-3K/Akt activity contributes to the resistance of human breast cancer cells to ionizing radiation and whether inhibition of the PI-3K/Akt pathway could sensitize human breast cancer cells to radiotherapy. To determine a causal relationship between the activity of Akt and radioresistance in human breast cancer cells, MCF7 cells, transfected with constitutively active H-Ras (RadG12V) or constitutively active Akt, were chosen for analysis of the cell clonogenic survival fraction and induction of apoptosis after ionizing radiation. The PI-3K-specific inhibitor LY294002 was used to examine whether inhibition of PI-3K could sensitize these cells to radiation treatment. Our results indicate that the expression of constitutively active Ras (which activated Akt in a PI-3K-dependent manner) and the expression of constitutively active Akt (which caused a PI-3K-independent activation of Akt) each increased cellular resistance to radiation. Inhibition of PI-3K with LY294002 reverted the constitutively active Ras-mediated radioresistance but not the constitutively active Akt-mediated radioresistance. Our data suggest that Akt may be a potential target for enhancing the response to radiotherapy in patients with breast cancer.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Liang
authors.forename: Weidong
authors.initials: W
authors.lastname: Jin
authors.forename: Christiane
authors.initials: C
authors.lastname: Knuefermann
authors.forename: Mathias
authors.initials: M
authors.lastname: Schmidt
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
authors.forename: Luka
authors.initials: L
authors.lastname: Milas
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000532:radiotherapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020287:In Situ Nick-End Labeling; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011839:Radiation, Ionizing; D014162:Transfection; D018631:ras Proteins / Q000378:metabolism
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human