Diet, Autophagy, and Cancer: A Review

Singletary, Keith W.; Milner, John

doi:10.1158/1055-9965.epi-07-2917

Cited by 146 publications

(106 citation statements)

References 215 publications

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“…In contrast, several other studies have demonstrated that autophagy has an anti-cancer effect. However, it is unclear whether autophagy is the mechanism for cell death or a reactive mechanism by which the cell is trying to survive the chemotherapy [27].…”

Section: Discussionmentioning

confidence: 99%

Oleuropein is a Powerful Sensitizer of Doxorubicin-mediated Killing of Prostate Cancer Cells and Exerts Its Action via Induction of Autophagy

Papachristodoulou¹,

Tsoukala²,

Benaki³

et al. 2018

JCRT

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The phenolic component Oleuropein (OLEU), a bioactive natural product, has recently shown antiproliferative properties. Doxorubicin (DXR) is an anthracycline present in many chemotherapeutic schemes, although limited due to its cardio-toxic effects. Important research effort has been devoted therefore, to reducing DXR toxicity without compromising its antitumor efficacy. The anticancer actions of DXR and OLEU were assessed, on PC-3 prostate cancer cells, while cell cycle distribution and rate of apoptosis were assessed by flow cytometry. The autophagic process was determined via immunoblotting and immunofluorescent staining. Finally, cell extracts were analyzed by NMR spectroscopy. The present study showed that both DXR and OLEU inhibited PC-3 cells proliferation, while the co-treatment with DXR and OLEU resulted in an additive inhibition. Although the addition of OLEU to DXR did not alter significantly the cell cycle distribution, exhibited by each treatment alone, and produced a marginal increase on the rate of apoptosis, both compounds produced a remarkable induction of autophagy. In addition, treated cells exhibited significant metabolite alterations. This study demonstrates that OLEU, a basic component of the everyday diet, is capable of lowering significantly the cytotoxic dose of DXR, while obtaining an important anti-proliferative effect in prostate cancer cells.

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Section: Discussionmentioning

confidence: 99%

Oleuropein is a Powerful Sensitizer of Doxorubicin-mediated Killing of Prostate Cancer Cells and Exerts Its Action via Induction of Autophagy

Papachristodoulou¹,

Tsoukala²,

Benaki³

et al. 2018

JCRT

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“…Previously, we developed CG-12, a thiazolidinedione-based ERMA that exhibits potency 3 orders of magnitude higher than 2-DG in inhibiting cancer cell proliferation through autophagy and apoptosis (8). Although it is well understood that AMPK activation plays a crucial role in ERMA-induced autophagy in cancer cells (33), the underlying mechanism of apoptosis remains unclear. Thus, CG-12 provides a useful pharmacological probe to understand the underlying signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Energy Restriction-mimetic Agents Induce Apoptosis in Prostate Cancer Cells in Part through Epigenetic Activation of KLF6 Tumor Suppressor Gene Expression

Chen

Huang²,

Chu

et al. 2011

Journal of Biological Chemistry

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Although energy restriction has been recognized as an important target for cancer prevention, the mechanism by which energy restriction-mimetic agents (ERMAs) mediate apoptosis remains unclear. By using a novel thiazolidinedione-derived ERMA, CG-12 (Wei, S., Kulp, S. K., and Chen, C. S. (2010) J. Biol. Chem. 285, 9780 -9791), vis-à-vis 2-deoxyglucose and glucose deprivation, we obtain evidence that epigenetic activation of the tumor suppressor gene Kruppel-like factor 6 (KLF6) plays a role in ERMA-induced apoptosis in LNCaP prostate cancer cells. KLF6 regulates the expression of many proapoptotic genes, and shRNA-mediated KLF6 knockdown abrogated the ability of ERMAs to induce apoptosis. Chromatin immunoprecipitation analysis indicates that this KLF6 transcriptional activation was associated with increased histone H3 acetylation and histone H3 lysine 4 trimethylation occupancy at the promoter region. Several lines of evidence demonstrate that the enhancing effect of ERMAs on these active histone marks was mediated through transcriptional repression of histone deacetylases and H3 lysine 4 demethylases by down-regulating Sp1 expression. First, putative Sp1-binding elements are present in the promoters of the affected histone-modifying enzymes, and luciferase reporter assays indicate that site-directed mutagenesis of these Sp1 binding sites significantly diminished the promoter activities. Second, shRNA-mediated knockdown of Sp1 mimicked the repressive effect of energy restriction on these histone-modifying enzymes. Third, ectopic Sp1 expression protected cells from the repressive effect of CG-12 on these histone-modifying enzymes, thereby abolishing the activation of KLF6 expression. Together, these findings underscore the intricate relationship between energy restriction and epigenetic regulation of tumor suppressor gene expression, which has therapeutic relevance to foster novel strategies for prostate cancer therapy.A hallmark feature of tumorigenesis is the shift of cellular metabolism from oxidative phosphorylation to aerobic glycolysis, the so-called Warburg effect, which provides a growth advantage to cancer cells in the microenvironment (1, 2). Recent evidence indicates that the high rate of glycolysis in tumor cells is attributable to the dysregulation of multiple oncogenic signaling pathways (1), including those mediated by hypoxia-inducible factor 1 (3), Akt (4), c-Myc (5), and p53 (6). This glycolytic shift is considered to be a fundamental property of neoplasia, and the high rate of glucose uptake in glycolytic tumor cells, including those of lung, breast, liver, and colon, is the basis for imaging tumors by [18 F]2-fluoro-2-deoxyglucose positron emission tomography (7). Moreover, in light of the in vivo efficacy of dietary caloric restriction and natural productbased energy restriction-mimetic agents (ERMAs) 2 such as 2-deoxyglucose (2-DG) and resveratrol in suppressing carcinogenesis in various animal models, targeting aerobic glycolysis represents a therapeutically relevant strategy for cancer prev...

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“…876,877 Interpreting the results of this type of research, however, warrants two cautionary notes. 878 First, the relationship between health status and autophagic activity is obviously far from being direct.…”

Section: Do Not Distributementioning

confidence: 97%

Guidelines for the use and interpretation of assays for monitoring autophagy

Klionsky¹,

Abdalla²,

Abeliovich³

et al. 2012

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In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

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Diet, Autophagy, and Cancer: A Review

Cited by 146 publications

References 215 publications

Oleuropein is a Powerful Sensitizer of Doxorubicin-mediated Killing of Prostate Cancer Cells and Exerts Its Action via Induction of Autophagy

Oleuropein is a Powerful Sensitizer of Doxorubicin-mediated Killing of Prostate Cancer Cells and Exerts Its Action via Induction of Autophagy

Energy Restriction-mimetic Agents Induce Apoptosis in Prostate Cancer Cells in Part through Epigenetic Activation of KLF6 Tumor Suppressor Gene Expression

Guidelines for the use and interpretation of assays for monitoring autophagy

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