Directed elimination of therapy-induced Senescent Cells by targeting Anti-Apoptotic Proteins in DLBCL

ABSTRACT

Different cancer chemotherapeutics can work by inducing apoptosis in cancer cells. Moreover, various tumor suppressors and oncogenes play a role in regulating senescence and apoptosis [1]. Senescent cells, formed in response to chemotherapeutic drugs, facilitate protection from lymphogenesis and aid in tissue repair [2]. Yet, the accumulation and chronic persistence of these cells promote adverse effects including chemoresistance and cancer relapse [3]. This demonstrates the importance of cell fate decision, apoptosis versus senescence, in determining the efficacy of therapeutic treatment not only in tumor clearance but also its recurrence. Here we established an in vitro senescence model using SU-DHL-4 lymphoma cells [DLBCL]. Our results showed that the exposure to the chemotherapeutic drug doxorubicin induces features of cellular senescence including cell cycle arrest, regulation of the tumor suppressor p53, resistance to apoptosis, secretion of various senescence-associated factors and positive beta-galactosidase staining. In addition, those senescent cells showed resistance to the treatment with cell-permeable peptide [Bcl-2/IP3R disruptor-2 [BIRD-2]] that targets the BH4 domain of BCL-2 potentiating pro-apoptotic calcium signaling in normal lymphoma cells. This suggests a calcium-dependent mechanism by which senescent cells resist apoptosis. We also revealed using Western blot analysis that senescent cells upregulate the antiapoptotic protein BCL-2. Inhibition of this protein using the small molecule ABT-737 specifically induced apoptosis in senescent cells. Reaching the conclusion that senescent cells can be eliminated pharmacologically paves the way towards new strategies to encounter cancer relapse due to chemoresistance