Concomitant reduction of c-Myc expression and PI3K/AKT/mTOR signaling by quercetin induces a strong cytotoxic effect against Burkitt’s lymphoma

Granato, Marisa; Rizzello, Celeste; Romeo, Maria Anele; Yadav, Shivangi; Santarelli, Roberta; D’Orazi, Gabriella; Faggioni, Alberto; Cirone, Mara

doi:10.1016/j.biocel.2016.09.006

Cited by 53 publications

(39 citation statements)

References 50 publications

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“…5A, forced expression of either ACER2 or p53 alone caused a remarkable induction of autophagy marker LC3-II. It has been well known that mTOR/Akt pathway plays an inhibitory role in autophagy1830. Consistently, the amounts of phosphor-mTOR and phosphor-Akt, which suppress autophagy, were decreased in H1299 cells expressing either ACER2 or p53, strongly suggesting that ACER2 has an ability to promote autophagy at least in part through the inhibition of mTOR-Akt pathway.…”

Section: Resultsmentioning

confidence: 57%

Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation

Wang

Zhang

Jin

et al. 2017

Sci Rep

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ACER2 is a critical sphingolipid metabolizing enzyme, and has been shown to be remarkably up-regulated following various stimuli such as DNA damage. However, the transcriptional regulatory mechanism of ACER2 gene and its potential role in the regulation of autophagy remain unknown. In this study, we have for the first time identified the human ACER2 gene promoter, and found that human ACER2 transcription is directly regulated by p53 and ACER2 is implicated in the induction of autophagy as well as apoptosis. A series of luciferase reporter assay demonstrated that ACER2 major promoter is located within its first intron where the consensus p53-binding sites exist. Consistently, forced expression of p53 significantly stimulated ACER2 transcription. Notably, p53-mediated autophagy and apoptosis were markedly enhanced by ACER2. Depletion of the essential autophagy gene ATG5 revealed that ACER2-induced autophagy facilitates its effect on apoptosis. Further studies clearly showed that ACER2-mediated autophagy and apoptosis are accompanied by ROS generation. In summary, our present study strongly suggests that ACER2 plays a pivotal role in p53-induced autophagy and apoptosis, and thus might serve as a novel and attractive molecular target for cancer treatment.

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Section: Resultsmentioning

confidence: 57%

Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation

Wang

Zhang

Jin

et al. 2017

Sci Rep

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“…The latter has been reported to be a target of apigenin in Primary Effusion Lymphoma (PEL) cells [ 7 ]. PEL is a Kaposi Sarcoma Associated Herpesvirus (KSHV)-associated malignant B cell lymphoma highly refractory to conventional chemotherapies [ 8 ], but displaying a good susceptibility to treatment with natural products such as capsaicin [ 9 , 10 ]. These molecules share the characteristic to concomitantly inhibit multiple oncogenic pathways such as AKT and STAT3, strongly involved in PEL cell survival [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Apigenin, by activating p53 and inhibiting STAT3, modulates the balance between pro-apoptotic and pro-survival pathways to induce PEL cell death

Granato

Montani

Santarelli

et al. 2017

J Exp Clin Cancer Res

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BackgroundApigenin is a flavonoid widely distributed in plant kingdom that exerts cytotoxic effects against a variety of solid and haematological cancers. In this study, we investigated the effect of apigenin against primary effusion lymphoma (PEL), a KSHV-associated B cell lymphoma characterized by a very aggressive behavior, displaying constitutive activation of STAT3 as well as of other oncogenic pathways and harboring wtp53.MethodsCell death was assessed by trypan blue exclusion assay, FACS analysis as well as by biochemical studies. The latter were also utilized to detect the occurrence of autophagy and the molecular mechanisms leading to the activation of both processes by apigenin. FACS analysis was used to measure the intracellular ROS utilizing DCFDA.ResultsWe show that apigenin induced PEL cell death and autophagy along with reduction of intracellular ROS. Mechanistically, apigenin activated p53 that induced catalase, a ROS scavenger enzyme, and inhibited STAT3, the most important pro-survival pathway in PEL, as assessed by p53 silencing. On the other hand, STAT3 inhibition by apigenin resulted in p53 activation, since STAT3 negatively influences p53 activity, highlighting a regulatory loop between these two pathways that modulates PEL cell death/survival.ConclusionThe findings of this study demonstrate that apigenin may modulate pro-apoptotic and pro-survival pathways representing a valid therapeutic strategy against PEL.

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“…30,31 Different studies showed that several compounds cause the arrest of proliferation and/or differentiation in Raji cell line by downregulation of c-MYC. [32][33][34] In this study, it was shown that I. viscosa extract is able to strongly reduce c-MYC expression and consequently CCND1 expression, as its targeted gene. Kozar et al 35 demonstrated that fibroblasts lacking all three D-type cyclins have very moderate defects in cell growth, although they cannot be transformed by MYC and RAS oncogenes.…”

Section: Discussionmentioning

confidence: 72%

Antiproliferative and proapoptotic effects of Inula viscosa extract on Burkitt lymphoma cell line

et al. 2020

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Burkitt lymphoma is a very aggressive B-cell non-Hodgkin lymphoma. Although remarkable progress has been made in the therapeutic scenario for patients with Burkitt lymphoma, search and development of new effective anticancer agents to improve patient outcome and minimize toxicity has become an urgent issue. In this study, the antitumoral activity of Inula viscosa, a traditional herb obtained from plants collected on the Asinara Island, Italy, was evaluated in order to explore potential antineoplastic effects of its metabolites on Burkitt lymphoma. Raji human cell line was treated with increasing Inula viscosa extract concentration for cytotoxicity screening and subsequent establishment of cell cycle arrest and apoptosis. Moreover, gene expression profiles were performed to identify molecular mechanisms involved in the anticancer activities of this medical plant. The Inula viscosa extract exhibited powerful antiproliferative and cytotoxic activities on Raji cell line, showing a dose- and time-dependent decrease in cell viability, obtained by cell cycle arrest in the G2/M phase and an increase in cell apoptosis. The treatment with Inula viscosa caused downregulation of genes involved in cell cycle and proliferation (c-MYC, CCND1) and inhibition of cell apoptosis (BCL2, BCL2L1, BCL11A). The Inula viscosa extract causes strong anticancer effects on Burkitt lymphoma cell line. The molecular mechanisms underlying such antineoplastic activity are based on targeting and downregulation of genes involved in cell cycle and apoptosis. Our data suggest that Inula viscosa natural metabolites should be further exploited as potential antineoplastic agents against Burkitt lymphoma.

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Concomitant reduction of c-Myc expression and PI3K/AKT/mTOR signaling by quercetin induces a strong cytotoxic effect against Burkitt’s lymphoma

Cited by 53 publications

References 50 publications

Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation

Alkaline ceramidase 2 is a novel direct target of p53 and induces autophagy and apoptosis through ROS generation

Apigenin, by activating p53 and inhibiting STAT3, modulates the balance between pro-apoptotic and pro-survival pathways to induce PEL cell death

Antiproliferative and proapoptotic effects of Inula viscosa extract on Burkitt lymphoma cell line

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