Combined Inhibition of Insulin Growth Factor 1 Receptor and Autophagy impede Colorectal Cancer Metastasis

Insulin-like growth factor 1 (IGF-1) is known to promote cancer cell proliferation, but its role in metastasis remains incompletely understood. Autophagy, a key regulator of cancer cell behavior, plays a significant role in colorectal cancer (CRC) progression. 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 CRC. However, the mechanistic contribution of IGF-1R to autophagy-driven CRC metastasis has not been fully elucidated. In this study, we investigated the functional interaction between IGF-1R signaling and autophagy in CRC progression using a panel of CRC cell lines, including HCT116 cells with CRISPR/Cas9-mediated knockout of ATG5 and ATG7. Our results demonstrate that IGF-1 stimulation enhances autophagic flux, whereas IGF-1R knockdown suppressed 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 increased size and number of focal adhesion molecules, such as paxillin and zyxin. 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. Further studies are warranted to delineate the underlying molecular mechanisms and evaluate these findings' translational potential in clinical settings.