Insulin-like growth factor I receptor prevents apoptosis and enhances neuroblastoma tumorigenesis.
Autocrine stimulation of the type I insulin-like growth factor receptor (IGF-IR) by IGF-II is one mechanism that allows cancer cells to maintain unregulated growth and to resist programmed cell death (PCD). SH-SY5Y and SHEP cells are cloned human neuroblastoma (NBL) lines originating from a single primary tumor. SH-SY5Y cells, which express abundant cell surface IGF-IR and produce IGF-II, exhibit serum independent growth and resist PCD due to hypoxia and hyperosmolar conditions. In contrast, SHEP cells, which produce no IGF-II and express five-fold fewer IGF-IRs, die in serum-free media or following exposure to metabolic stressors. To better understand the roles of IGF-IR and its ligand, IGF-II, in NBL carcinogenesis, we stably transfected SHEP cells with either IGF-II or IGF-IR. Unregulated expression of IGF-II did not alter the growth characteristics of SHEP/human IGF-II transfectants. In contrast, overexpression of IGF-IR allowed SHEP/IGF-IR transfectants to survive in media supplemented only by IGF-II. IGF-IR abundance correlated in a graded fashion with resistance to PCD in response to three different death-inducing paradigms: mitogen withdrawal, hyperosmolar metabolic stress, and treatment with etoposide. Our results suggest that adjuvant therapy aimed at reducing IGF-IR abundance may enhance chemotherapy-coupled apoptosis in the treatment of NBL.
Singleton
J R
JR
University of Michigan, Department of Neurology, Ann Arbor 48109, USA.
Randolph
A E
AE
Feldman
E L
EL
D017209:Apoptosis / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured
D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1