@Article{biocell.2024.047871,
AUTHOR = {JIYU WANG, LIUYING YI, KEKE HUANG, YANGYANG WANG, HUIPING WANG, ZHIMIN ZHAI},
TITLE = {<i>SENEX</i>-mediated CDK4/6 inhibition promotes senescence and confers apoptosis resistance in B-cell non-Hodgkin lymphoma},
JOURNAL = {BIOCELL},
VOLUME = {48},
YEAR = {2024},
NUMBER = {3},
PAGES = {453--462},
URL = {http://www.techscience.com/biocell/v48n3/55719},
ISSN = {1667-5746},
ABSTRACT = { <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.},
DOI = {10.32604/biocell.2024.047871}
}