NFE2L2 and STAT3 Converge on Common Targets to Promote Survival of Primary Lymphoma Cells

Abstract

NFE2L2 and STAT3 are key pro-survival molecules, and thus, their targeting may represent a promising anti-cancer strategy. In this study, we found that a positive feedback loop occurred between them and provided evidence that their concomitant inhibition efficiently impaired the survival of PEL cells, a rare, aggressive B cell lymphoma associated with the gammaherpesvirus KSHV and often also EBV. At the molecular level, we found that NFE2L2 and STAT3 converged in the regulation of several pro-survival molecules and in the activation of processes essential for the adaption of lymphoma cells to stress. Among those, STAT3 and NFE2L2 promoted the activation of pathways such as MAPK3/1 and MTOR that positively regulate protein synthesis, sustained the antioxidant response, expression of molecules such as MYC, BIRC5, CCND1, and HSP, and allowed DDR execution. The findings of this study suggest that the concomitant inhibition of NFE2L2 and STAT3 may be considered a therapeutic option for the treatment of this lymphoma that poorly responds to chemotherapies.

5-AZA Upregulates SOCS3 and PTPN6/SHP1, Inhibiting STAT3 and Potentiating the Effects of AG490 against Primary Effusion Lymphoma Cells

“…Previous studies have shown that the inhibition of STAT3 Y705 tyrosine phosphorylation, mainly mediated by Janus activating kinases (JAK) 2, may be an effective strategy for reducing the survival of PEL cells [ 5 , 6 ]. Notably, STAT3 engages in crosstalk with other pro-survival pathways, e.g., nuclear factor erythroid 2–related factor 2 (NRF2) [ 7 ] and mutant p53 [ 8 , 9 ], to further promote tumorigenesis; on the other hand, it may negatively influence the activation of wtp53 in PEL cells [ 10 ]. Other than phosphorylation, STAT3 may undergo other post-translational modifications that affect its activity, and among those, it may be acetylated [ 11 ] or methylated [ 12 , 13 ].…”