Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition.
Akt, a downstream effector kinase of insulin receptor and insulin-like growth factor-I receptor (IGF-IR), is critically involved in epithelial-mesenchymal transition (EMT). The aim of this study was to assess the impact of SLUG in the IGF/IGF-IR/Akt axis. The SLUG-overexpressing MDCK (SLUG-MDCK) cell clones were used as the EMT model. In contrast to the parental cells and mock-transfected MDCK cells, SLUG-MDCK cells were markedly sensitive to IGFs, showing a clear tyrosine-phosphorylation in IGF-IR under serum-starved conditions. The IGF-IR of hepatocytes was highly activated by culture supernatants from SLUG-MDCK cells. This activation was inhibited by IGF-binding protein (IGFBP)-3, and by the IGF-IR inhibitor PQ401, leading to inactivation of Akt. This finding suggested establishment of autocrine IGF-IR signaling in the SLUG-MDCK cells. It is known that cells overexpressing receptor tyrosine kinases have an increased activity in Src kinase, which constitutively phosphorylates IGF-IR. In the present study, we found an increased phosphorylation of Src in SLUG-MDCK cells, and not in mock-MDCK cells; however, this Src activation was not always coupled with the constitutive activation of IGF-IR, since the specific Src inhibitor PP2 failed to decrease the IGF-IR phosphorylation. PP2 just attenuated the phosphorylation in Akt, not through IGF-IR inactivation, leading to apoptosis in SLUG-MDCK cells. Of interest, the inactivation of Akt by IGFBP-3 was dramatically enhanced in combination with the use of PP2, resulting in a significant apoptosis in SLUG-MDCK cells. These findings suggested that dual targeting for IGF-IR and Src might be a potential therapeutic strategy in EMT-driven aggressive cancers.
Sivakumar
Ramadoss
R
Research Center for Innovative Cancer Therapy, Department of Medicine, Kurume University, Kurume 830-0011, Japan.
Koga
Hironori
H
Selvendiran
Karuppaiyah
K
Maeyama
Michiko
M
Ueno
Takato
T
Sata
Michio
M
D000818:Animals; D002460:Cell Line; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000502:physiology; D008648:Mesoderm / Q000166:cytology*; D010006:Osteoblasts / Q000502:physiology*; D010766:Phosphorylation; D034622:RNA Interference; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D017526:Receptor, IGF Type 1