The Knockdown of FKBP Prolyl Isomerase 10 (FKBP10) Reverses Resistance in BRAFV600E Mutant Thyroid Papillary Cancer Cells

Abstract

Background and Objective: Vemurafenib (VEM) is commonly used to treat papillary thyroid cancer (PTC) with the B-Raf proto-oncogene, serine/threonine kinase (BRAF)^V600E mutation. However, a major challenge during treatment is the emergence of cellular resistance to vemurafenib. Furthermore, FKBP Prolyl Isomerase 10 (FKBP10) has been associated with the occurrence and progression of various cancer types. Therefore, the current study aimed to investigate the role of FKBP10 in the emergence of cellular resistance to vemurafenib within PTC patients. Methods: The potential of FKBP10 in the proliferation of VEM-resistant cells was assessed in vitro using the Cell Counting Kit-8 (CCK-8), colony formation, and cell migration assays. Western blotting, Co-Immunoprecipitation, Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), and confocal immunofluorescence labeling assay were employed to investigate the underlying molecular mechanism of FKBP10 overexpression in VEM-resistant cells. Results: Compared to Nthy-ori 3-1, expression levels of FKBP10 were substantially increased in PTC cells. Furthermore, the knockdown of FKBP10 significantly increased their drug sensitivity. However, resistant cell lines exhibited a significant reduction in cell survival, migration, and colony formation (p < 0.05) and elevated apoptotic rate. Additionally, silencing FKBP10 (sh-FKBP10) significantly decreased the expression levels of p-Protein kinase B (AKT) and p-Phosphoinositide 3-kinase (pI3K) in human thyroid cancer papillary cells (p < 0.05). Similarly, treatment with PI3K inhibitor LY294002 and AKT inhibitor MK-2206 substantially decreased the expression levels of the p-AKT and p-pI3K proteins (p < 0.05) and hence reduced cell survival. Furthermore, Co-Immunoprecipitation (Co-IP) and confocal microscopy experiments revealed a significant interaction between the PI3K/AKT signaling pathway and FKBP10. Conclusions: The present study shows that vemurafenib resistance can be reversed through FKBP10 knockdown.