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Effect of Vitamin D on Relapse-Free Survival in a Subgroup of Patients with p53 Protein-Positive Digestive Tract Cancer: A Post Hoc Analysis of the AMATERASU Trial.
Akutsu, T, Okada, S, Hirooka, S, Ikegami, M, Ohdaira, H, Suzuki, Y, Urashima, M
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020;(2):406-413
Abstract
BACKGROUND The AMATERASU randomized trial of vitamin D3 supplementation (2,000 IU/day; UMIN000001977) showed the potential benefit of vitamin D in a subgroup of patients with digestive tract cancer. By conducting post hoc analyses of this trial, we further explored whether subgroups stratified by expression levels of p53, vitamin D receptor (VDR), and Ki-67 modify the effect of vitamin D supplementation. METHODS The primary outcome was relapse-free survival (RFS). On IHC using pathologic specimens, the degree of p53 protein expression parallel with TP53 missense mutations was classified as p53 positive (>10%) and p53 negative (≤10%). In addition, VDR and Ki-67 expression levels were divided into quartiles. RESULTS The p53 status of 372 patients' pathologic specimens was evaluated. In a subgroup of patients with p53-positive cancer (n = 226), 5-year RFS was 79% in the vitamin D group, which was significantly higher than the 57% in the placebo group (HR, 0.52; 95% confidence interval, 0.31-0.88; P = 0.02). In the subgroup of patients with p53-negative cancer, 5-year RFS in the vitamin D group versus placebo group was 72% versus 84% (not significantly different), respectively. Effect modification by p53 positivity was significant (P interaction = 0.02). However, no significant effect modification by either VDR or Ki-67 was observed. CONCLUSIONS These results generate a hypothesis that vitamin D supplementation may improve RFS in patients with p53-positive digestive tract cancer. IMPACT The results are still preliminary, but potentially important, because TP53 is the most frequently mutated gene across cancers at all sites.
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Deferasirox-Dependent Iron Chelation Enhances Mitochondrial Dysfunction and Restores p53 Signaling by Stabilization of p53 Family Members in Leukemic Cells.
Calabrese, C, Panuzzo, C, Stanga, S, Andreani, G, Ravera, S, Maglione, A, Pironi, L, Petiti, J, Shahzad Ali, MS, Scaravaglio, P, et al
International journal of molecular sciences. 2020;(20)
Abstract
Iron is crucial to satisfy several mitochondrial functions including energy metabolism and oxidative phosphorylation. Patients affected by Myelodysplastic Syndromes (MDS) and acute myeloid leukemia (AML) are frequently characterized by iron overload (IOL), due to continuous red blood cell (RBC) transfusions. This event impacts the overall survival (OS) and it is associated with increased mortality in lower-risk MDS patients. Accordingly, the oral iron chelator Deferasirox (DFX) has been reported to improve the OS and delay leukemic transformation. However, the molecular players and the biological mechanisms laying behind remain currently mostly undefined. The aim of this study has been to investigate the potential anti-leukemic effect of DFX, by functionally and molecularly analyzing its effects in three different leukemia cell lines, harboring or not p53 mutations, and in human primary cells derived from 15 MDS/AML patients. Our findings indicated that DFX can lead to apoptosis, impairment of cell growth only in a context of IOL, and can induce a significant alteration of mitochondria network, with a sharp reduction in mitochondrial activity. Moreover, through a remarkable reduction of Murine Double Minute 2 (MDM2), known to regulate the stability of p53 and p73 proteins, we observed an enhancement of p53 transcriptional activity after DFX. Interestingly, this iron depletion-triggered signaling is enabled by p73, in the absence of p53, or in the presence of a p53 mutant form. In conclusion, we propose a mechanism by which the increased p53 family transcriptional activity and protein stability could explain the potential benefits of iron chelation therapy in terms of improving OS and delaying leukemic transformation.
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Circulating Antibodies against Epstein-Barr Virus (EBV) and p53 in EBV-Positive and -Negative Gastric Cancer.
Camargo, MC, Kim, KM, Matsuo, K, Torres, J, Liao, LM, Morgan, D, Michel, A, Waterboer, T, Song, M, Gulley, ML, et al
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2020;(2):414-419
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Abstract
BACKGROUND Epstein-Barr virus (EBV)-positive gastric cancers have clinicopathologic differences from EBV-negative tumors and lack TP53 mutation. Serologic profiles may inform viral contribution to carcinogenesis. METHODS We compared humoral responses of EBV-positive (n = 67) and EBV-negative (n = 137) patients with gastric cancer from the International EBV-Gastric Cancer Consortium. Serum antibodies against four EBV proteins, nuclear (EBNA), viral capsid (VCA), early-diffuse (EA-D), and Zta replication activator (ZEBRA), and to p53 were assessed by multiplex assays. OR of antibody level tertiles (T1-T3) were adjusted by logistic regression. We also conducted a meta-analysis of reported anti-p53 seropositivity in gastric cancer. RESULTS Consistent with EBV's ubiquity, 99% of patients were seropositive for anti-EBNA and 98% for anti-VCA, without difference by tumor EBV status. Seropositivity varied between patients with EBV-positive and EBV-negative tumors for anti-EA-D (97% vs. 67%, respectively, P < 0.001) and anti-ZEBRA (97% vs. 85%, respectively, P = 0.009). Adjusted ORs (vs. T1) for patients with EBV-positive versus EBV-negative tumors were significantly elevated for higher antibodies against EBNA (2.6 for T2 and 13 for T3), VCA (1.8 for T2 and 2.4 for T3), EA-D (6.0 for T2 and 44 for T3), and ZEBRA (4.6 for T2 and 12 for T3). Antibodies to p53 were inversely associated with EBV positivity (3% vs. 15%; adjusted OR = 0.16, P = 0.021). Anti-p53 prevalence from the literature was 15%. CONCLUSIONS These serologic patterns suggest viral reactivation in EBV-positive cancers and identify variation of p53 seropositivity by subtype. IMPACT Anti-EBV and anti-p53 antibodies are differentially associated with tumor EBV positivity. Serology may identify EBV-positive gastric cancer for targeted therapies.
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A ruthenium(II)-curcumin compound modulates NRF2 expression balancing the cancer cell death/survival outcome according to p53 status.
Garufi, A, Baldari, S, Pettinari, R, Gilardini Montani, MS, D'Orazi, V, Pistritto, G, Crispini, A, Giorno, E, Toietta, G, Marchetti, F, et al
Journal of experimental & clinical cancer research : CR. 2020;(1):122
Abstract
BACKGROUND 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. 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. METHODS We 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. RESULTS We 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. CONCLUSIONS These 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.
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Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction.
Rasafar, N, Barzegar, A, Mehdizadeh Aghdam, E
Scientific reports. 2020;(1):11449
Abstract
MDM2 and MDMX are known as overexpressed oncoproteins in several wild-type p53 cancer cells. The development of potent and dual antagonist peptides for p53-MDM2/X is a continuous challenge. In this study, we intended to investigate the pivotal structural points respecting the development of potent and dual inhibitors of MDM2/X. Correspondingly, MD simulation was performed on the experimentally confirmed peptides, comprising p53, pDI, pDIQ, PMI, and computationally screened mutant pDI and pDIQ. A follow-up secondary structure analysis showed the last three C-terminal residues provide the helicity reservation of peptides bound to MDM2/X. Furthermore, a delicate residue-residue examination displayed Met 11 and Ser12 in the modified peptides contribute significantly to dual inhibition of MDM2/X. Additionally, the peptides_MDM2/X complexes' ΔGbinding extracted by the umbrella sampling method were in agreement with the pattern of their experimental affinity values. It was concluded the screened pDI mutants were considered as suitable anti-MDM2/X peptides, and the data obtained could be exploited as the theoretical structure-based guide for rational peptide design. Taking account of results, the suitable C-terminal residues of p53-based peptides especially Met11, and Ser12, as well as higher umbrella sampling, generated ΔGbinding to MDM2/X would be considered as the positive structural markers of a promising anti-cancer agent.
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Regulating tumor suppressor genes: post-translational modifications.
Chen, L, Liu, S, Tao, Y
Signal transduction and targeted therapy. 2020;(1):90
Abstract
Tumor suppressor genes cooperate with each other in tumors. Three important tumor suppressor proteins, retinoblastoma (Rb), p53, phosphatase, and tensin homolog deleted on chromosome ten (PTEN) are functionally associated and they regulated by post-translational modification (PTMs) as well. PTMs include phosphorylation, SUMOylation, acetylation, and other novel modifications becoming growing appreciated. Because most of PTMs are reversible, normal cells use them as a switch to control the state of cells being the resting or proliferating, and PTMs also involve in cell survival and cell cycle, which may lead to abnormal proliferation and tumorigenesis. Although a lot of studies focus on the importance of each kind of PTM, further discoveries shows that tumor suppressor genes (TSGs) form a complex "network" by the interaction of modification. Recently, there are several promising strategies for TSGs for they change more frequently than carcinogenic genes in cancers. We here review the necessity, characteristics, and mechanisms of each kind of post-translational modification on Rb, p53, PTEN, and its influence on the precise and selective function. We also discuss the current antitumoral therapies of Rb, p53 and PTEN as predictive, prognostic, and therapeutic target in cancer.
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KLF5 regulates epithelial-mesenchymal transition of liver cancer cells in the context of p53 loss through miR-192 targeting of ZEB2.
Sun, L, Zhou, X, Li, Y, Chen, W, Wu, S, Zhang, B, Yao, J, Xu, A
Cell adhesion & migration. 2020;(1):182-194
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Abstract
Krüppel-like factor 5 (KLF5) can both promote and suppress cell migration, but the underlying mechanisms have not been elucidated. In this study, we show that the function of KLF5 in epithelial-mesenchymal transition (EMT) and migration of liver cancer cells depends on the status of the cellular tumor antigen p53 (p53). Furthermore, zinc finger E-box-binding homeobox 2 (ZEB2) is the main regulator of KLF5 in EMT in liver cancer cells in the context of p53 loss. Most importantly, the regulation of ZEB2 by p53 and KLF5 is indirect and that miR-192 mediates this regulation. Finally, we find that in invasive liver cancer, KLF5 is absent in the context of p53 loss or mutation.
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Par-4 regulates autophagic cell death in human cancer cells via upregulating p53 and BNIP3.
Thayyullathil, F, Cheratta, AR, Pallichankandy, S, Subburayan, K, Tariq, S, Rangnekar, VM, Galadari, S
Biochimica et biophysica acta. Molecular cell research. 2020;(7):118692
Abstract
Prostate apoptosis response-4 (Par-4) is a tumor suppressor protein that selectively induces apoptosis in cancer cells. Although the mechanism of Par-4-mediated induction of apoptosis has been well studied, the involvement of Par-4 in other mechanisms of cell death such as autophagy is unclear. We investigated the mechanism involved in Par-4-mediated autophagic cell death in human malignant glioma. We demonstrate for the first time that the tumor suppressor lipid, ceramide (Cer), causes Par-4 induction, leading to autophagic cell death in human malignant glioma. Furthermore, we identified the tumor suppressor protein p53 and BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) as downstream targets of Par-4 during Cer-mediated autophagic cell death. RNAi-mediated down-regulation of Par-4 blocks Cer-induced p53-BNIP3 activation and autophagic cell death, while upregulation of Par-4 augmented p53-BNIP3 activation and autophagic cell death. Remarkably, in many instances, Par-4 overexpression alone was sufficient to induce cell death which is associated with features of autophagy. Interestingly, similar results were seen when glioma cells were exposed to classical autophagy inducers such as serum starvation, arsenic trioxide, and curcumin. Collectively, the novel Par-4-p53-BNIP3 axis plays a crucial role in autophagy-mediated cell death in human malignant glioma.
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Pentamidine niosomes thwart S100B effects in human colon carcinoma biopsies favouring wtp53 rescue.
Seguella, L, Rinaldi, F, Marianecci, C, Capuano, R, Pesce, M, Annunziata, G, Casano, F, Bassotti, G, Sidoni, A, Milone, M, et al
Journal of cellular and molecular medicine. 2020;(5):3053-3063
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Abstract
S100B protein bridges chronic mucosal inflammation and colorectal cancer given its ability to activate NF-kappaB transcription via RAGE signalling and sequestrate pro-apoptotic wtp53. Being an S100B inhibitor, pentamidine antagonizes S100B-wtp53 interaction, restoring wtp53-mediated pro-apoptotic control in cancer cells in several types of tumours. The expression of S100B, pro-inflammatory molecules and wtp53 protein was evaluated in human biopsies deriving from controls, ulcerative colitis and colon cancer patients at baseline (a) and (b) following S100B targeting with niosomal PENtamidine VEhiculation (PENVE), to maximize drug permeabilization in the tissue. Cultured biopsies underwent immunoblot, EMSA, ELISA and biochemical assays for S100B and related pro-inflammatory/pro-apoptotic proteins. Exogenous S100B (0.005-5 μmol/L) alone, or in the presence of PENVE (0.005-5 μmol/L), was tested in control biopsies while PENVE (5 μmol/L) was evaluated on control, peritumoral, ulcerative colitis and colon cancer biopsies. Our data show that S100B level progressively increases in control, peritumoral, ulcerative colitis and colon cancer enabling a pro-inflammatory/angiogenic and antiapoptotic environment, featured by iNOS, VEGF and IL-6 up-regulation and wtp53 and Bax inhibition. PENVE inhibited S100B activity, reducing its capability to activate RAGE/phosphor-p38 MAPK/NF-kappaB and favouring its disengagement with wtp53. PENVE blocks S100B activity and rescues wtp53 expression determining pro-apoptotic control in colon cancer, suggesting pentamidine as a potential anticancer drug.
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The vicious cycle between ferritinophagy and ROS production triggered EMT inhibition of gastric cancer cells was through p53/AKT/mTor pathway.
Xu, Z, Feng, J, Li, Y, Guan, D, Chen, H, Zhai, X, Zhang, L, Li, C, Li, C
Chemico-biological interactions. 2020;:109196
Abstract
Cancer metastasis and resistance for chemotherapeutic agent correlate with epithelial-mesenchymal transition (EMT), while ROS production also involves in the EMT process, However, how autophagy mediated ROS production affects EMT remains unclear. Previous study showed that DpdtC (2,2'-di-pyridylketone hydrazone dithiocarbamate) could induce ferritinophagy in HepG2 cell. To insight into more details that how ferritinophagy affects cellular feature, the SGC-7901and BGC-823 gastric cancer cell lines were used. Interestingly DpdtC treatment resulted in EMT inhibition and was ROS dependent. Similar situation occurred in TGF-β1 induced EMT model, supporting that DpdtC was able to inhibit EMT. Next the ability of DpdtC in ferritinophagy induction was further evaluated. As expected, DpdtC induced ferritinophagy in the absence and presence of TGF-β1. The correlation analysis revealed that an enhanced ferritinophagic flux contributed to the EMT inhibition. In addition, ferritinophagy triggers Fenton reaction, resulting in ROS production which give rise of p53 response, thus the role of p53 was further investigated. DpdtC treatment resulted in upregulation of p53, but, the addition of p53 inhibitor, PFT-α could significantly neutralize the action of DpdtC on ferritinophagy induction and EMT inhibition. Furthermore, autophagy inhibitors or NAC could counteract the action of DpdtC, indicating that ferrtinophagy-mediated ROS played an important role in the cellular events. In addition to upregulation of p53, its down-stream targets, AKT/mTor were also downregulated, supporting that DpdtC induced EMT inhibition was achieved through ferritinophagy-ROS vicious cycle mediated p53/AKT/mTor pathway. And the activation of ferritinophagic flux was the dominant driving force in action of DpdtC in gastric cancer cells.