1. Academic Validation
  2. IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas

IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas

  • Signal Transduct Target Ther. 2020 Aug 26;5(1):153. doi: 10.1038/s41392-020-0204-0.
Qing Wang 1 Yan Zhang 1 Jiang Zhu 1 2 2 Honggang Zheng 3 Shuntai Chen 3 Li Chen 4 Hsin-Sheng Yang 5 6
Affiliations

Affiliations

  • 1 Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY, USA.
  • 2 Department of Breast Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
  • 3 Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
  • 4 Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA.
  • 5 Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY, USA. hyang3@uky.edu.
  • 6 Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY, USA. hyang3@uky.edu.
Abstract

The insulin-like growth factor 1 receptor (IGF-1R) governs several signaling pathways for cell proliferation, survival, and anti-apoptosis. Thus, targeting IGF-1R appears as a reasonable rationale for tumor treatment. However, clinical studies showed that inhibition of IGF-1R has very limited efficacy due to the development of resistance to IGF-1R blockade in tumor cells. Here, we discovered that prolonged treatment of colon Cancer cells with IGF-1R inhibitors (BMS-754807 and GSK1838705A) stimulates p70 KDa ribosomal protein S6 kinase 1 (p70S6K1) activation, a well-known kinase signaling for cell survival. We also found that p70S6K1 activation by IGF-1R inhibition is independent of K-Ras and PIK3CA mutations that frequently occur in colon Cancer. Besides the increased p70S6K1 phosphorylation, the phosphorylation of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) was elevated in the cells treated with BMS-754807. Interestingly, the increases in MEK1/2 and p70S6K1 phosphorylation were also observed when cells were subjected to the treatment of Akt Inhibitor or genetic knockdown of Akt2 but not Akt1, suggesting that Akt2 inhibition stimulates MEK1/2 phosphorylation to activate p70S6K1. Conversely, inhibition of MEK1/2 by MEK1/2 inhibitor (U0126) or knockdown of MEK1 and MEK2 by corresponding MEK1 and MEK2 siRNA enhanced Akt phosphorylation, indicating mutual inhibition between Akt and MEK. Furthermore, the combination of BMS-754807 and U0126 efficiently decreased the cell viability and increased cleaved Caspase 3 and Apoptosis in vitro and in vivo. Our data suggest that the treatment of colon tumor cells with IGF-1R inhibitors stimulates p70S6K1 activity via MEK1/2 to promote survival, providing a new strategy for colorectal Cancer therapeutics.

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