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sENEX-mediated CDK4/6 inhibition promotes senescence and confers apoptosis resistance in B-cell non-Hodgkin lymphoma

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BIOCELL 2024年第3期48卷 453-462页

作者： JIYU WANg LIUYINg YI KEKE HUANg YANgYANg WANg HUIPINg WANg ZHIMIN ZHAI Department of Hematology The Second Affiliated Hospital of Anhui Medical UniversityHefei230601China Department of Hematology The Fourth Affiliated HospitalZhejiang University School of MedicineYiwu322000China

Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIs)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed sENEX/Rho gTPase Activating Protein 18(ARHgAP18)expression and prognostic signiﬁcance in doxorubicin-induced B-NHL-TIs model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining speciﬁc inhibitors on apoptosis resistance in B-NHL-TIs cells.Methods:Raji cells were transfected with the human sENEX shRNA recombinant lentiviral vector(sh-sENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of sENEX.Effect of sENEX-silencing on B-NHL-TIs formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the speciﬁc cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIs formation.sENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of sENEX expression promotes g1-s phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIs in B-NHL.Blockade of CDK4/6 promotes the DOX-induced g1 phase arrest to enhance TIs formation in B-NHL cells which can reverse the regulatory effect of silencing sENEX on B-NHL cell cycle regulation and senescence.The expression levels of sENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of sENEX were associated with poor prognosis of B-NHL patients.Conclusions:sENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing g1-s phase transition and promoting TIs formation.

关键词： sENEX B-cell non-Hodgkin lymphoma CDK4/6 g1-s phase transition Therapy-induced senescence Apoptosis resistance

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