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<p>The role of Insulin-like growth factor 1 (IGF-1) in promoting cancer proliferation has been identified, yet its potential role in metastasis has not been fully elucidated. Autophagy plays a pivotal, yet controversial, role in regulating cancer cell behaviour. Our previous transcriptomic analysis identified autophagy-related genes and insulin-like growth factor 1 receptor (IGF-1R) among the most differentially expressed in advanced versus early-stage colorectal cancer (CRC). In this study, we investigated the functional interplay between IGF-1R signalling and autophagy in CRC progression and metastasis, using a panel of CRC cell lines, including HCT116 cells with targeted CRISPR-Cas9 knockout of ATG5 and ATG7. Our results demonstrate that stimulation with IGF-1 enhances autophagic flux, whereas IGF-1R knockdown suppresses autophagic activity. Notably, dual inhibition of IGF-1R and autophagy led to a marked reduction in CRC cell migration and invasion. In ATG5-/- and ATG7-/- cells, IGF-1R silencing significantly downregulated mesenchymal markers Vimentin, Slug, and Snail, while upregulating the epithelial marker E-cadherin. Additionally, combined inhibition resulted in increased size and number of focal adhesion molecules, such as paxillin and zyxin. Collectively, these findings highlight the synergistic effect of IGF-1R and autophagy inhibition in suppressing EMT and metastatic potential in CRC cells, suggesting that this combinatorial approach may represent a promising therapeutic strategy for metastatic CRC.</p> Graphical abstract <p></p>

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Combined inhibition of insulin growth factor 1 receptor and autophagy prevents colorectal cancer metastasis

  • 期刊论文

  • 发表日期：

    2025年12月26日

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  • Eglal Mahgoub,
  • Khuloud Bajbouj,
  • Samrein Ahmed,
  • Shirin Hafezi,
  • Leen Eldohaji,
  • Thenmozhi Venkatachalam,
  • Mahmood Hachim,
  • Tasneem Al Hamidi,
  • Jasmin Shafarin,
  • Wael M. Abdel-Rahman,
  • Nabil Sulaiman,
  • Rifat Hamoudi,
  • Jalal Taneera,
  • Ritu Lakhtakia,
  • Iman M. Talaat,
  • Maha Saber-Ayad

摘要

The role of Insulin-like growth factor 1 (IGF-1) in promoting cancer proliferation has been identified, yet its potential role in metastasis has not been fully elucidated. Autophagy plays a pivotal, yet controversial, role in regulating cancer cell behaviour. Our previous transcriptomic analysis identified autophagy-related genes and insulin-like growth factor 1 receptor (IGF-1R) among the most differentially expressed in advanced versus early-stage colorectal cancer (CRC). In this study, we investigated the functional interplay between IGF-1R signalling and autophagy in CRC progression and metastasis, using a panel of CRC cell lines, including HCT116 cells with targeted CRISPR-Cas9 knockout of ATG5 and ATG7. Our results demonstrate that stimulation with IGF-1 enhances autophagic flux, whereas IGF-1R knockdown suppresses autophagic activity. Notably, dual inhibition of IGF-1R and autophagy led to a marked reduction in CRC cell migration and invasion. In ATG5-/- and ATG7-/- cells, IGF-1R silencing significantly downregulated mesenchymal markers Vimentin, Slug, and Snail, while upregulating the epithelial marker E-cadherin. Additionally, combined inhibition resulted in increased size and number of focal adhesion molecules, such as paxillin and zyxin. Collectively, these findings highlight the synergistic effect of IGF-1R and autophagy inhibition in suppressing EMT and metastatic potential in CRC cells, suggesting that this combinatorial approach may represent a promising therapeutic strategy for metastatic CRC.

Graphical abstract