TY - JOUR
T1 - Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors
T2 - Therapeutic implications
AU - Chang, Qing
AU - Li, Yu
AU - White, Morris F.
AU - Fletcher, Jonathan A.
AU - Xiao, Sheng
PY - 2002/11/1
Y1 - 2002/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0036828097&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036828097&partnerID=8YFLogxK
M3 - Article
C2 - 12414625
AN - SCOPUS:0036828097
SN - 0008-5472
VL - 62
SP - 6035
EP - 6038
JO - Cancer Research
JF - Cancer Research
IS - 21
ER -