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Phosphoinositide 3-hydroxide kinase blockade enhances apoptosis in the Ewing's sarcoma family of tumors.
- Source :
-
Cancer research [Cancer Res] 1999 Nov 15; Vol. 59 (22), pp. 5745-50. - Publication Year :
- 1999
-
Abstract
- Ewing's sarcoma family of tumors (ESFTs) affects patients between the ages of 3 and 40 years, with most cases occurring in the second decade of life. These tumors contain a characteristic translocation, t(11;22), that produces a unique fusion protein, EWS/FLI-1. EWS/FLI-1 transforms mouse fibroblasts; this transformation requires intact EWS and FLI-1 domains as well as the insulin-like growth factor-I receptor (IGF-IR). The IGF-IR is a well-described transmembrane tyrosine kinase receptor that modulates transformation, cell growth, and survival. IGF-IR survival signaling is mediated through the downstream activation of phosphoinositide 3-OH kinase (PI 3-K) and Akt. Apoptosis, programmed cell death, progresses from a central death signal to a caspase cascade, including activation of caspase-3. Because the IGF-IR has been shown to play a role in the transformation and growth of ESFTs, we wanted to determine the role of downstream molecules in the cellular response to doxorubicin treatment. Doxorubicin increased caspase-3 activity in two ESFT cell lines, TC-32 and TC-71. Concomitant treatment of the doxorubicin-treated cells with IGF-I reduced caspase-3 activity 8-fold in TC-32 and 4-fold in TC-71. To determine whether PI 3-K has a role in IGF-I-mediated survival in ESFTs, PI 3-K was then inhibited with wortmannin and LY294002. Doxorubicin treatment reduced cell number and enhanced apoptosis in PI 3-K inhibited cells compared with noninhibited cells. Akt, a serine/threonine kinase activated downstream of PI 3-K, was investigated to determine whether its constitutive activation would render ESFT cells more resistant to doxorubicin. A constitutively activated Akt was stably transfected into ESFT and those cells with high levels of expression demonstrated increased resistance to doxorubicin-induced caspase-3 activation. These results indicate that ESFT cell lines use an IGF-IR initiated signaling pathway through PI 3-K and Akt for survival when treated with doxorubicin.
- Subjects :
- Androstadienes pharmacology
Antineoplastic Agents antagonists & inhibitors
Antineoplastic Agents pharmacology
Caspase 3
Cell Transformation, Neoplastic chemically induced
DNA Fragmentation
Doxorubicin antagonists & inhibitors
Doxorubicin pharmacology
Enzyme Activation drug effects
Enzyme Inhibitors pharmacology
Humans
In Situ Nick-End Labeling
Insulin-Like Growth Factor I pharmacology
Neoplasm Proteins metabolism
Phosphatidylinositol 3-Kinases metabolism
Protein Serine-Threonine Kinases physiology
Proto-Oncogene Proteins c-akt
Receptor, IGF Type 1
Sarcoma, Ewing physiopathology
Tumor Cells, Cultured drug effects
Wortmannin
Apoptosis genetics
Caspases metabolism
Neoplasm Proteins antagonists & inhibitors
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins
Sarcoma, Ewing enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 59
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 10582694