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

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 cell...

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Published in:International journal of molecular sciences 2023-07, Vol.24 (14), p.11598
Main Authors: Arena, Andrea, Di Crosta, Michele, Gonnella, Roberta, Zarrella, Roberta, Romeo, Maria Anele, Benedetti, Rossella, Gilardini Montani, Maria Saveria, Santarelli, Roberta, D'Orazi, Gabriella, Cirone, Mara
Format: Article
Language:English
Subjects:
Autophagy
Cancer
Cancer therapies
Care and treatment
Cell growth
Computer software industry
Cytotoxicity
DNA damage
DNA repair
Enzymes
Heat shock proteins
Humans
Kinases
Lymphocytes - metabolism
Lymphoma
Lymphoma, B-Cell
Lymphomas
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Oncology, Experimental
Phosphorylation
Protein biosynthesis
Protein synthesis
STAT3 Transcription Factor - metabolism
Transcription factors
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241411598