Inositol hexaphosphate enhances chemotherapy by reversing persistent endoplasmic reticulum stress-induced senescence through decreasing P-PERK and ADPr-eEF-2 levels in colorectal cancer

Abstract Background Oxaliplatin is an important initial chemotherapy benefiting advanced-stage colorectal cancer patients. Frustratingly, acquired resistance always occurs after sequential chemotherapy, accompanied by endoplasmic reticulum stress activation. Because endoplasmic reticulum stress occurs in both chemoresistant and chemosensitive tumor cells, the correlation between endoplasmic reticulum stress and chemoresistance are needed to be explored in-depth. Methods Flow cytometry, CCK8, and immunoblot were employed to evaluate the oxaliplatin resistance models. RNA-Seq, STRING analysis and SA-β-gal staining were used to prove the key role of Protein kinase R-like endoplasmic reticulum kinase (PERK) in the development of endoplasmic reticulum and senescence. Tissue specimens from colorectal cancer patients were used to determine the expression levels and prognostic values of phosphorylated PERK. Inositol hexaphosphate from FDA-approved antioxidants library was selected through molecular docking in silico to evaluate their affinity for endoplasmic reticulum stress sensors. Surface plasmon resonance was performed to confirm their affinity for endoplasmic reticulum stress sensors. In vitro and in vivo functional experiments were carried out to explore the role of inositol hexaphosphate in colorectal cancer chemoresistance. Results The formation of oxaliplatin-resistant colorectal cancer with increased cell senescence was contributed to persistent ER stress. Moreover, PERK was a key negative regulator in the malignant progression of colorectal cancer, acting as a key role in ER stress, cell senescence, and chemoresistance. Inositol hexaphosphate had a strong affinity for DPH1 and GRP78 and orchestrated UPR by decreasing P-PERK and ADPr-eEF-2 levels. Finally, inositol hexaphosphate enhanced killing of chemoresistant cells by modulating UPR in colorectal cancer under ER stress. Conclusions Oxaliplatin resistance contributed to cell senescence induced by persistent endoplasmic reticulum stress. Chemoresistance and senescence in colorectal cancer were specifically reversed by combination therapy with inositol hexaphosphate relating to decreased P-PERK and ADPr-eEF-2 levels.