Open Access

ARTICLE

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

JIYU WANG^1,#, LIUYING YI^2,#, KEKE HUANG¹, YANGYANG WANG¹, HUIPING WANG¹, ZHIMIN ZHAI^1,*

1 Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China
2 Department of Hematology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, China

* Corresponding Author: ZHIMIN ZHAI. Email:
# These authors have contributed equally to this work

(This article belongs to the Special Issue: Navigating the Interplay of Cancer, Autophagy, ER Stress, Cell Cycle and Apoptosis: Mechanisms, Therapies, and Future Directions)

BIOCELL 2024, 48(3), 453-462. https://doi.org/10.32604/biocell.2024.047871

Received 20 November 2023; Accepted 23 January 2024; Issue published 15 March 2024

Abstract

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.

---

Keywords

---