Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications.
Insulin receptor substrate 1 (IRS-1) is a major substrate of insulin, insulin-like growth factors, and cytokine signaling and plays an important role in mediating apoptosis, cell differentiation, and cell transformation. We found that IRS-1 is constitutively activated in a variety of solid tumors, including breast cancers, leiomyomas, Wilms' tumors, rhabdomyosarcomas, liposarcomas, leiomyosarcomas, and adrenal cortical carcinomas. Blocking the constitutively activated IRS-1 signaling in breast cancer cells with a dominant-negative IRS-1, an IRS-1 with all 18 potential tyrosine-phosphorylation sites replaced by phenylalanines (F18), dramatically reduced cancer cell growth. Breast cancer cells that expressed F18 also formed smaller and far fewer colonies in soft agar culture than did the cells that did not express F18. These studies suggest that constitutive IRS-1 activation is a common phenomenon in tumors and that activated IRS-1 may present an attractive therapeutic target.
Chang
Qing
Q
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Li
Yu
Y
White
Morris F
MF
Fletcher
Jonathan A
JA
Xiao
Sheng
S
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin