Hypoxia-driven signaling contributes substantially to therapy resistance in colorectal cancer, in part through activation of the PERK-mediated stress response. The present study examined whether pharmacological inhibition of PERK produces selective anti-tumor effects in colon cancer cells and influences apoptosis-related pathways.

Human HT-29 colorectal carcinoma cells and non-malignant CCD 841 CoN colon epithelial cells were exposed to increasing concentrations of a PERK inhibitor for 16, 24, and 48 hours. Cellular viability was evaluated using standard cytotoxicity assays. Changes in PERK-associated stress response genes were quantified by qPCR and verified at the protein level by Western blotting. Cell-cycle alterations were assessed through cyclin D1 expression analysis.

Treatment with the PERK inhibitor resulted in a dose-dependent reduction in HT-29 cell viability across all incubation periods, with the strongest effect observed at concentrations up to 50 µM. In contrast, normal CCD 841 CoN cells showed no detectable loss of viability under identical conditions, indicating cancer-selective activity and lack of toxicity toward healthy colon epithelium. Molecular analyses revealed that the PERK blockade in hypoxic HT-29 cells elevated expression of ATF4, DDIT3/CHOP, and BCL2L11/BIM, while suppressing anti-apoptotic BCL2. Additionally, cyclin D1 levels were markedly reduced following PERK inhibition under hypoxia, consistent with cell-cycle arrest at the G2/M transition and impaired progression into G1.

Collectively, these findings demonstrate that PERK inhibition selectively compromises survival of hypoxic colon cancer cells while sparing normal tissue, supporting PERK as a promising therapeutic target in colorectal cancer.

This study was funded by the National Science Centre (NCN), Poland, PRELUDIUM grant no. 2015/19/N/NZ3/00055.