Regulation of autophagy by polyphenolic compounds as a potential therapeutic strategy for cancer

Hasima, Noor; Özpolat, Bülent

doi:10.1038/cddis.2014.467

Cited by 235 publications

(191 citation statements)

References 128 publications

(145 reference statements)

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“…The data from the present study demonstrated that the overexpression of Beclin-1 may inhibit tumor cell migration, which also suggests that Beclin-1 expression is associated with tumor invasion in gastric cancer. Novel autophagy-based interventions, including Bcl-2 family regulation, caspase-dependent cleavage of autophagy-related gene protein and microRNA mimics to downregulate Beclin-1 have already been clinically or experimentally applied, suggesting promising approaches for novel clinical treatments (30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

Beclin‑1 suppresses gastric cancer progression by promoting apoptosis and reducing cell migration

et al. 2017

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Abstract. To investigate Beclin-1 expression in gastric cancer and its clinical relevance, 60 samples were collected from patients with gastric carcinoma, which were subjected to immunohistochemical staining and analysis. Associations of Beclin-1 expression with the clinical parameters of the patients, including tumor size, histological differentiation and metastatic status, were examined by statistical analysis. The results demonstrated that Beclin-1 expression in gastric carcinoma tissue was significantly associated with the tumor, node, metastasis stage and tumor invasion status. Further experiments indicated that Beclin-1 overexpression promoted MKN-45 gastric cancer cell apoptosis and inhibited their migration. These data suggested that Beclin-1 was a suppressor of tumorigenesis in gastric cancer and a potential therapeutic target for patients with gastric cancer. IntroductionAutophagy serves an important role in maintaining cell metabolism and homeostasis (1). Autophagy is a process of endogenous substrate digestion in cells; autophagosomes are formed, and mature proteins or damaged organelles in the cytoplasm are encased by lysosomes, in which lysosomal proteases degrade them.During tumorigenesis and tumor progression, autophagy exerts its role as a tumor suppressor by removing abnormally folded proteins and dysfunctional organelles such as mitochondria, inhibiting cell stress responses (2). However, in instances of nutritional deficiencies and hypoxia, autophagy supports tumor cell survival, which promotes cell proliferation and suppresses cell death (3). Compromised autophagy promotes chromosomal instability, including increased DNA damage, gene amplification and aneuploidy (4).As a key autophagy regulator associated with apoptosis and differentiation, the autophagy-associated protein Beclin-1 has been demonstrated to be involved in many types of cancer, including ovarian carcinoma (5), hepatocellular carcinoma (6), melanoma (7), rectal cancer (8) and tongue squamous cell carcinoma (9). It has been suggested that the endogenous Beclin-1 protein expression is frequently low in human breast epithelial carcinoma cell lines and tissues, whereas it is expressed ubiquitously at high levels in normal breast epithelia (10). Concomitantly, the autophagy-promoting activity in the MCF7 breast cancer cell line following transfection with Beclin-1 was observed to inhibit MCF7 proliferation, clonogenicity and tumorigenesis (10). A previous in vivo study demonstrated that mice with inactivated or deleted Beclin-1 were susceptible to tumors including lymphoma, lung cancer and liver cancer (11,12).Beclin-1 modulates cancer initiation and progression by affecting a wide range of pathological events, including extracellular matrix degradation, epithelial-to-mesenchymal transition, tumor angiogenesis and alterations to the tumor microenvironment (13). However, the effect of Beclin-1 in cancer development is complex, as a number of reports have indicated the pro-neoplastic and anti-neoplastic functions for Beclin-1, as revi...

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Section: Discussionmentioning

confidence: 99%

Beclin‑1 suppresses gastric cancer progression by promoting apoptosis and reducing cell migration

et al. 2017

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“…While apoptosis fulfills this role by removing damaged or unwanted cells, autophagy maintains cellular homeostasis by recycling selective intracellular organelles and proteins, and thus is considered an important protective mechanism for cancer cells in response to chemotherapy [25] . However, autophagy may help to induce apoptosis under certain conditions or lead to a non-apoptotic form of programmed cell death (PCD) called autophagic cell death or autophagyassociated cell death (type II PCD) [26] . Thus, the function of autophagy as cell death or cell survival machinery in different cases needs to be established.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol analogue 3,4,4′-trihydroxy-trans-stilbene induces apoptosis and autophagy in human non-small-cell lung cancer cells in vitro

et al. 2015

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Aim:To investigate the effects of 3,4,4′-trihydroxy-trans-stilbene (3,4,4′-THS), an analogue of resveratrol, on human non-small-cell lung cancer (NSCLC) cells in vitro. Methods: Cell viability of NSCLC A549 cells was determined by MTT assay. Cell apoptosis was evaluated using flow cytometry and TUNEL assay. Cell necrosis was evaluated with LDH assay. The expression of apoptosis-or autophagy-associated proteins was measured using Western blotting. The formation of acidic compartments was detected using AO staining, neutral red staining and Lysotracker-Red staining. LC3 punctae were analyzed with fluorescence microscopy. Results: Treatment with 3,4,4′-THS (10-80 μmol/L) concentration-dependently inhibited the cell viability. It did not cause cell necrosis, but induced apoptosis accompanied by up-regulation of cleavaged PARP, caspase3/9 and Bax, and by down-regulation of Bcl-2 and surviving. It also increased the formation of acidic compartments, LC3-II accumulation and GFP-LC3 labeled autophagosomes in the cells. It inhibited the mTOR-dependent pathway, but did not impair autophagic flux. 3,4,4′-THS-induced cell death was enhanced by the autophagy inhibitors 3-MA (5 mmol/L) or Wortmannin (2 μmol/L). Moreover, 3,4,4′-THS treatment elevated the ROS levels in the cells, and co-treatment with 3-MA further elevated the ROS levels. 3,4,4′-THS-induced apoptosis and autophagy in the cells was attenuated by NAC (10 mmol/L) Conclusion: 3,4,4′-THS induces both apoptosis and autophagy in NSCLC A549 cells in vitro. Autophagy inhibitors promote 3,4,4′-THSinduced apoptosis of A549 cells, thus combination of 3,4,4′-THS and autophagy inhibitor provides a promising strategy for NSCLC treatment.

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“…On the other hand, Opipari et al presented the first evidence that resveratrol promotes cell death via autophagy in five ovarian cancer cell lines, which implied resveratrol as a promising regime in treating apoptosis-resistant cancer cells [166]. In addition, quercetin has antitumorigenic effects linked to its capacity for targeting key tumorigenic pathways such as mTOR/ elF4E-BP1/P70S6K signaling in ovarian cancer [167]. All the evidence demonstrates that many phytochemical compounds present in diets not only are inherently lesser toxicity but may also give novel therapeutic strategies in the treatment of ovarian cancer.…”

Section: Nutraceuticals and Traditional Medicinesmentioning

confidence: 99%

Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

Yung

Ngan

Chan

2016

ABBS

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The development and strategic application of effective anticancer therapies have turned out to be one of the most critical approaches of managing human cancers. Nevertheless, drug resistance is the major obstacle for clinical management of these diseases especially ovarian cancer. In the past years, substantial studies have been carried out with the aim of exploring alternative therapeutic approaches to enhance efficacy of current chemotherapeutic regimes and reduce the side effects caused in order to produce significant advantages in overall survival and to improve patients' quality of life. Targeting cancer cell metabolism by the application of AMP-activated protein kinase (AMPK)-activating agents is believed to be one of the most plausible attempts. AMPK activators such as 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside, A23187, metformin, and bitter melon extract not only prevent cancer progression and metastasis but can also be applied as a supplement to enhance the efficacy of cisplatin-based chemotherapy in human cancers such as ovarian cancer. However, because of the undesirable outcomes along with the frequent toxic side effects of most pharmaceutical AMPK activators that have been utilized in clinical trials, attentions of current studies have been aimed at the identification of replaceable reagents from nutraceuticals or traditional medicines. However, the underlying molecular mechanisms of many nutraceuticals in anticancer still remain obscure. Therefore, better understanding of the functional characterization and regulatory mechanism of natural AMPK activators would help pharmaceutical development in opening an area to intervene ovarian cancer and other human cancers.

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Regulation of autophagy by polyphenolic compounds as a potential therapeutic strategy for cancer

Cited by 235 publications

References 128 publications

Beclin‑1 suppresses gastric cancer progression by promoting apoptosis and reducing cell migration

Beclin‑1 suppresses gastric cancer progression by promoting apoptosis and reducing cell migration

Resveratrol analogue 3,4,4′-trihydroxy-trans-stilbene induces apoptosis and autophagy in human non-small-cell lung cancer cells in vitro

Targeting AMPK signaling in combating ovarian cancers: opportunities and challenges

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