EGCG antagonizes Bortezomib cytotoxicity in prostate cancer cells by an autophagic mechanism

Modernelli, Alice; Naponelli, Valeria; Troglio, Maria Giovanna; Bonacini, Martina; Ramazzina, Ileana; Bettuzzi, Saverio; Rizzi, Federica

doi:10.1038/srep15270

Cited by 65 publications

(52 citation statements)

References 52 publications

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“…Similar effects have been described for two synthetic enantiomeric analogs of natural GTCs in PCa cells [133]. The observed accumulation of short-lived proteins, normally addressed to proteosomal degradation such as p21, p27, Bax and ikΒα, in PCa cells after EGCG or GTCs treatment indirectly confirms, that GTCs exert inhibitory effect on the proteasome activity [98,134].…”

Section: Proteasome Inhibitionsupporting

confidence: 73%

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges

Naponelli¹,

Ramazzina²,

Lenzi³

et al. 2017

Preprint

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Green Tea Catechins (GTCs) are a family of chemically related compounds usually classified as antioxidant molecules. Epidemiological evidences, supported by interventional studies, highlighted a more than promising role for GTCs in human Prostate Cancer (PCa) chemoprevention.In the last decades many efforts have been made to gain new insights into the mechanism of action of GTCs. Now it is clear that GTCs anticancer action can no longer be simplistically limited to their direct antioxidant/pro-oxidant properties. Recent contributions to the advancement of knowledge in this field have shown that GTCs specifically interact with cellular targets including, cell surface receptors, lipid rafts and endoplasmic reticulum, modulate gene expression through direct effect on transcription factors or indirect epigenetic mechanisms, interfere with intracellular proteostasis at various levels. Many of the effects observed in vitro are dose and cell context dependent and take place at concentration that cannot be achieved in vivo.Poor intestinal absorption together with an extensive systemic and enteric metabolism influence GTCs bioavailability through still poor understood mechanisms. Recent efforts to develop delivery systems that increase GTCs overall bioavailability, by mean of biopolymeric nanoparticles, represent the main way to translate preclinical results in a real clinical scenario for PCa chemoprevention.

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Section: Proteasome Inhibitionsupporting

confidence: 73%

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges

Naponelli¹,

Ramazzina²,

Lenzi³

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

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“…We next examined whether p21 induction was mediated by the inhibition of autophagy-induced protein degradation after treatment with CQ or AQ [24–26]. As previously reported [27,28], CQ treatment increased the level of the autophagosome membrane-bound form of LC3B. AQ also strongly increased the level of LC3B degradation via autophagy but had no effect on ATG5 expression (Fig.…”

Section: Resultsmentioning

confidence: 70%

Anti-inflammatory activity of chloroquine and amodiaquine through p21-mediated suppression of T cell proliferation and Th1 cell differentiation

Shin

Jang

et al. 2016

Biochemical and Biophysical Research Communications

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Chloroquine (CQ) and amodiaquine (AQ) have been used for treating or preventing malaria for decades, and their application has expanded into treating inflammatory disease in humans. CQ and AQ are applicable for controlling rheumatoid arthritis, but their molecular mechanisms of anti-inflammatory activity remain to be elucidated. In this study, we examined the effects of CQ and AQ on T cell activation and T cell-mediated immune response. CQ had no significant effect on T cell numbers, but decreased the population of T cells with a high division rate. However, AQ treatment significantly increased the number of cells with low division rates and eliminated cells with high division rates, resulting in the inhibition of T cell proliferation triggered by T cell receptor stimulation, of which inhibition occurred in developing effector T helper and regulatory T cells, regardless of the different exogenous cytokines. Interestingly, the cyclin-dependent kinase inhibitor p21 was significantly and dose-dependently increased by CQ, and more potently by AQ, while other cell cycle regulators were unchanged. Both CQ and AQ elevated the transcription level of p21 though the activation of p53, but also blocked p21 protein degradation in the presence of cycloheximide, causing p21 protein accumulation mainly in the nucleus. Sustained treatment of developing T cells with either CQ or AQ suppressed IFN-γ production in a dose dependent manner and potently inhibited the differentiation of IFN-γ-producing Th1 cells. These results demonstrate that CQ and AQ increase the expression level of p21 and inhibit T cell proliferation and the development of IFN-γ-producing Th1 cells, thereby revealing beneficial roles in treating a wide range of chronic inflammatory diseases mediated by inflammatory T cells.

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“…Recently, it has been suggested that autophagy plays a critical role in the resistance of PCa cells to hormonal therapy or chemotherapy and that inhibition of autophagy synergizes with docetaxel or androgen deprivation [15,16]. Combined treatment of several different cancer cell lines with autophagy suppressive agents and bortezomib increases cell death and improves clinical response in patients with relapsed multiple myeloma [17–19]. Further, proteasome inhibitor-resistant PCa cells are thought to utilize autophagy to resist this class of drugs [20].…”

Section: Introductionmentioning

confidence: 99%

C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome–lysosome fusion

et al. 2016

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The purpose of this study was to ascertain the mechanisms by which advanced prostate cancer cells resist bortezomib therapy. Several independent studies have shown that cells are protected from proteasome inhibition by increased autophagic activity. We investigated whether C/EBPβ, a transcription factor involved in the control of autophagic gene expression, regulates resistance to proteasome inhibition. In PC3 cells over-expressing C/EBPβ, turnover of autophagic substrates and expression of core autophagy genes were increased. Conversely, C/EBPβ knockdown suppressed autophagosome–lysosome fusion. We also found that C/EBPβ knockdown suppressed REDD1 expression to delay early autophagy, an effect rescued by exogenous REDD1. Cells with suppressed C/EBPβ levels showed delayed autophagy activation upon bortezomib treatment. Knockdown of C/EBPβ sensitized PC3 cells to bortezomib, and blockade of autophagy by chloroquine did not further increase cell death in cells expressing shRNA targeting C/EBPβ. Lastly, we observed a decreased growth of PC3 cells and xenografts with C/EBPβ knockdown and such xenografts were sensitized to bortezomib treatment. Our results demonstrate that C/EBPβ is a critical effector of autophagy via regulation of autolysosome formation and promotes resistance to proteasome inhibitor treatment by increasing autophagy.

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EGCG antagonizes Bortezomib cytotoxicity in prostate cancer cells by an autophagic mechanism

Cited by 65 publications

References 52 publications

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges

Green Tea Catechins for Prostate Cancer Prevention: Present Achievements and Future Challenges

Anti-inflammatory activity of chloroquine and amodiaquine through p21-mediated suppression of T cell proliferation and Th1 cell differentiation

C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome–lysosome fusion

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