TNF-α inhibits the chemotherapy resistance caused by upregulation of the PERK-ATF4 pathway in colorectal cancer cells

The unfolded protein response (UPR) is a set of important pathways important for maintaining endoplasmic reticulum homeostasis. Recent evidence suggests that the UPR plays an important role in chemo-resistance. However, the underlying mechanisms are not well understood. We previously found that the PERK pathway, one of three branches of the UPR pathway, is crucial for the resistance of colorectal cancer (CRC) cells to 5-fluorouracil. In this study, we demonstrated that activating transcription factor 4 (ATF4), the key downstream factor of the PERK pathway, is overexpressed in human CRCs and associated with a poor prognosis. Loss of ATF4 sensitized CRC cells to multiple chemotherapy drugs. RNA-seq analysis revealed that the TNF-α signaling pathway was significantly induced upon chemotherapy drug treatment while repressed by ATF4-knockdown. Addition of TNF-α can further potentiate the cytotoxic effects of chemotherapy drugs to ATF4-knockdown cells, highlighting a potential role of the TNF-α signaling pathway in regulating the ATF4-mediated drug sensitivity modulation. In summary, our findings provide a promising approach to overcoming chemotherapy resistance in colon cancer.