SHP2 induced 125I radiotherapy-resistant in cervical cancer via modulating ERK/E2F1/SKP2 and P53/AMPK/FOXO signaling induced apoptosis and proliferation

Abstract To elucidate the molecular mechanismthrough which SHP2 confers resistance to 125I radiotherapy in cervical cancer by promoting the ERK/E2F1/SKP2 pathway while antagonizing the P53/AMPK/FOXO pathway. Bioinformatics analysis was employed to identify SHP2 associated genes.In vivo experiments assessed tumor progression via subcutaneous tumor transplantation in nude mice. In vitro experiments included Western blot analysis and immunofluorescence staining to quantify protein expression levels, flow cytometry to evaluate apoptosis and proliferation, and Transwell assays to measure cell migration and invasion capabilities. 125I radiotherapy in cervical cancer induces DNA damage, activating the P53 signaling pathway. P53 transcriptionally suppresses SHP2 expression while simultaneously activating LKB1, which, through the LKB1/AMPK axis, upregulates FOXO1/FOXO3a transcription factors, thereby enhancing the expression of pro-apoptotic genes. Concurrently, RTK-mediated phosphorylation of SHP2 activates the RAS/ERK/CDK signaling cascade, leading to E2F1 activation. E2F1 not only drives the expression of DNA repair genes to mitigate radiation-induced damage but also transcriptionally upregulates SKP2, which mediates the ubiquitination and degradation of FOXO1/FOXO3a, thereby suppressing apoptosis. SHP2 attenuates apoptosistic signals and enhances cellular proliferation by activating the ERK/E2F1/SKP2 pathwaywhile inhibiting the P53/AMPK/FOXO pathway, ultimately conferring resistance to 125I radiotherapy.