Abstract
BackgroundTumor progression and tumor response to anticancer therapies may be affected by activation of oncogenic pathways such as the antioxidant one induced by NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor and the pathways modified by deregulation of oncosuppressor p53. Often, oncogenic pathways may crosstalk between them increasing tumor progression and resistance to anticancer therapies. Therefore, understanding that interplay is critical to improve cancer cell response to therapies. In this study we aimed at evaluating NRF2 and p53 in several cancer cell lines carrying different endogenous p53 status, using a novel curcumin compound since curcumin has been shown to target both NRF2 and p53 and have anti-tumor activity.MethodsWe performed biochemical and molecular studies by using pharmacologic of genetic inhibition of NRF2 to evaluate the effect of curcumin compound in cancer cell lines of different tumor types bearing wild-type (wt) p53, mutant (mut) p53 or p53 null status.ResultsWe found that the curcumin compound induced a certain degree of cell death in all tested cancer cell lines, independently of the p53 status. At molecular level, the curcumin compound induced NRF2 activation, mutp53 degradation and/or wtp53 activation. Pharmacologic or genetic NRF2 inhibition further increased the curcumin-induced cell death in both mutp53- and wtp53-carrying cancer cell lines while it did not increase cell death in p53 null cells, suggesting a cytoprotective role for NRF2 and a critical role for functional p53 to achieve an efficient cancer cell response to therapy.ConclusionsThese findings underline the prosurvival role of curcumin-induced NRF2 expression in cancer cells even when cells underwent mutp53 downregulation and/or wtp53 activation. Thus, NRF2 inhibition increased cell demise particularly in cancer cells carrying p53 either wild-type or mutant suggesting that p53 is crucial for efficient cancer cell death. These results may represent a paradigm for better understanding the cancer cell response to therapies in order to design more efficient combined anticancer therapies targeting both NRF2 and p53.
Highlights
Tumor progression and tumor response to anticancer therapies may be affected by activation of oncogenic pathways such as the antioxidant one induced by Nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor and the pathways modified by deregulation of oncosuppressor p53
(See figure on previous page.) Fig. 2 ruthenium(II)-curcumin compound (RuCUR) compound reduced mutant p53 levels that correlated with reduced proliferation and increased cell death. (a) Mutp53-carrying T98 and SKBR3 cells were seeded on ultra-low attachment multiwell plates allowing for tumor spheroid formation
Histograms represent the fold increase quantified with respect to controls set to 1.0, ± standard deviation (SD). * (p ≤ 0.01), # (p ≤ 0.05). (b) Cell viability was measured by trypan blue exclusion assay in T98 and SKBR3 cells treated for 24 h with different doses of RuCUR (1, 10, 50, 100 μM) and expressed as cell death percentage ± S.D. * (p ≤ 0.01), # (p ≤ 0.05). (c) Western blot analysis of p53 protein was performed in T98 and SKBR3 cells untreated or treated with RuCUR (1, 10, 50, 100 μM) for 24 h
Summary
Tumor progression and tumor response to anticancer therapies may be affected by activation of oncogenic pathways such as the antioxidant one induced by NRF2 (nuclear factor erythroid 2-related factor 2) transcription factor and the pathways modified by deregulation of oncosuppressor p53. Mutp oncogenic activities ma depend by modifications of the tumor microenvironment altering the secretion of inflammatory cytokines that affect the crosstalk between cancer and stromal cells [25, 26] or by interaction with other transcription factors such as NRF2 (nuclear factor erythroid 2-related factor 2, encoded by NFE2L2 gene) or HIF-1 (hypoxia-inducible factor 1) to support tumor progression and resistance to therapies [27]. Understanding the interplay between these oncogenic pathways may have an impact on the development of more efficient targeted anticancer therapies
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