TY  - EJOU
AU  - WANG, JIYU 
AU  - YI, LIUNG 
AU  - HUANG, KEKE 
AU  - WANG, YANGYANG 
AU  - WANG, HUIPING 
AU  - ZHAI, ZHIMIN 

TI  - <i>SENEX</i>-mediated CDK4/6 inhibition promotes senescence and confers apoptosis resistance in B-cell non-Hodgkin lymphoma
T2  - BIOCELL

PY  - 2024
VL  - 48
IS  - 3
SN  - 1667-5746

AB  -  <b>Background:</b> 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 <i>SENEX</i>/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. <b>Methods:</b> Raji cells were transfected with the human <i>SENEX</i> shRNA recombinant lentiviral vector (Sh-<i>SENEX</i>) and the empty vector negative (NC) to construct a stable transfection cell line with knockdown of <i>SENEX</i>. Effect of <i>SENEX</i>-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. <i>SENEX</i> 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. <b>Results:</b> The downregulation of <i>SENEX</i> 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 <i>SENEX</i> on B-NHL cell cycle regulation and senescence. The expression levels of <i>SENEX</i> were notably elevated in B-NHL patients compared to healthy controls, and Elevated expression levels of <i>SENEX</i> were associated with poor prognosis of B-NHL patients. <b>Conclusions:</b> <i>SENEX</i> enhances apoptosis resistance in B-NHL by inhibiting CDK4/6, thereby preventing G1-S phase transition and promoting TIS formation.
KW  - <i>SENEX</i>; B-cell non-Hodgkin lymphoma; CDK4/6; G1-S phase transition; Therapy-induced senescence; Apoptosis resistance

DO  - 10.32604/biocell.2024.047871