Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition

  • Authors:
    • Ramadoss Sivakumar
    • Hironori Koga
    • Karuppaiyah Selvendiran
    • Michiko Maeyama
    • Takato Ueno
    • Michio Sata
  • View Affiliations

  • Published online on: February 1, 2009     https://doi.org/10.3892/ijo_00000155
  • Pages: 329-338
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Abstract

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.

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February 2009
Volume 34 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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APA
Sivakumar, R., Koga, H., Selvendiran, K., Maeyama, M., Ueno, T., & Sata, M. (2009). Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition. International Journal of Oncology, 34, 329-338. https://doi.org/10.3892/ijo_00000155
MLA
Sivakumar, R., Koga, H., Selvendiran, K., Maeyama, M., Ueno, T., Sata, M."Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition". International Journal of Oncology 34.2 (2009): 329-338.
Chicago
Sivakumar, R., Koga, H., Selvendiran, K., Maeyama, M., Ueno, T., Sata, M."Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition". International Journal of Oncology 34, no. 2 (2009): 329-338. https://doi.org/10.3892/ijo_00000155