Study On The Mechanism Of CD317 Targeting Enhancing The Sensitivity Of Bortezomib In The Treatment Of Hematomai

ObjectiveMultiple myeloma(MM),the second most common hematologic malignancy,is characterized by abnormal transformation and growth of plasma cells in the bone marrow.The emergence of several therapeutic agents,including proteasome inhibitors(PIs)and immunomodulators(IMIDs),has significantly improved the efficacy of MM.However,almost all patients with MM become difficult to treat and relapse due to newly developed resistance.Therefore,finding ways to improve drug sensitivity or prevent drug resistance has become an important research course.MethodsHematoma cells(K562,Jurkat,H929)with high expression of CD317 were selected for this study.After transfection with CD317-specific si RNA for 36-48 hours,cytosolic and endoplasmic reticulum Ca2+ levels and bortezomib(BTZ)-induced cell death were detected by flow cytometry.Realtime PCR,Western blot,immunoprecipitation and other techniques were used to detect the expression of ER stress-related genes,accumulation of misfolded proteins,activation of related signaling pathways and interactions among Calnexin proteins.By which systematically study the effect of CD317 on the anti-hemoma effect of BTZ and the underlying mechanisms.Results1.CD317 is highly expressed in various hematoma cells and protects hemomatoma cells from BTZ-induced cell death.2.CD317 knockdown impairs proteostasis of tumor cells.3.CD317 knockdown affected the calcium balance between cytoplasm and endoplasmic reticulum.4.CD317 binds to calnexin thereby promotes the autophagic degradation of calnexin.5.Calnexin knockdown alleviates calcium disorder and protein misfolding caused by CD317 dysfunction.ConclusionsOur results indicate that CD317 is a key protein for maintaining proteostasis in hemomatoma cells.CD317 knockdown impaired the autophagic degradation of Calnexin,resulting in calcium imbalance between cytoplasmic and endoplasmic reticulum and misfolded protein accumulation.Thus,CD317 knockdown cells are more sensitive to BTZ due to its fragile proteostasis,which suggests targeting CD317 can enhance the anti-hemoma effect of BTZ.Conclusive,our findings not only elucidate the mechanism of CD317 regulating proteostasis,but also provide new theoretical guidelines and candidate scheme for overcoming bortezomib resistance...