Suppression of autophagy by chloroquine sensitizes 5-fluorouracil-mediated cell death in gallbladder carcinoma cells

Liang, Xiao; Tang, Jiancheng; Liang, Yuelong; Jin, Renan; Cai, Xiujun

doi:10.1186/2045-3701-4-10

Cited by 66 publications

(49 citation statements)

References 40 publications

(33 reference statements)

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“…c-Jun N-terminal kinases (JNK) activation and phosphorylation of Bcl-2 have been demonstrated as key components in 5-FU-induced autophagy in colon cancer [89] , where 5-FU-induced autophagy protects cancer cells [87] . Similar findings have been shown in gallbladder carcinoma, where 5-FU also induced autophagy, and inhibition of autophagy with chloroquine was able to kill cancer cells [91] . Similar findings have been demonstrated in a range of other cancers, including estrogen receptor-positive breast cancer where autophagy inhibition can re-sensitise breast cancer cells to tamoxifen [92] .…”

Section: Autophagy and Drug Resistancesupporting

confidence: 81%

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

Hill¹,

Wang²

2019

CDR

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Epithelial-mesenchymal transition (EMT) and autophagy are both known to play important roles in the development of cancer. Subsequently, these processes are now being utilised as targets for therapy. Cancer is globally one of the leading causes of death, and, despite many advances in treatment options, patients still face many challenges. Drug resistance in cancer-therapy is a large problem, and both EMT and autophagy have been shown to contribute. However, given the context-dependent role of these processes and the complexity of the interactions between them, elucidating how they both act alone and interact is important. In this review, we provide insight into the current landscape of the interactions of autophagy and EMT in the context of malignancy, and how this ultimately may affect drug resistance in cancer therapy.

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Section: Autophagy and Drug Resistancesupporting

confidence: 81%

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

Hill¹,

Wang²

2019

CDR

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“…AQ and related compounds sharing a 4-amino-7-chloroquinoline scaffold are well-known antimalarial drugs, and have also been shown to display neuroprotective activity by protecting dopaminergic neurons from injury by environmental toxins and microglia-dependent neuroinflammation (40). Additionally, these compounds have been shown to regulate autophagy such that long-term use of these compounds would need to be carefully evaluated (59). Beneficial metabolic effects of these compounds have not, to our knowledge, been reported.…”

Section: Discussionmentioning

confidence: 99%

NURR1 activation in skeletal muscle controls systemic energy homeostasis

Amoasii

Fujikawa

Elmquist

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Skeletal muscle plays a central role in the control of metabolism and exercise tolerance. Analysis of muscle enhancers activated after exercise in mice revealed the orphan nuclear receptor NURR1/ NR4A2 as a prominent component of exercise-responsive enhancers. We show that exercise enhances the expression of NURR1, and transgenic overexpression of NURR1 in skeletal muscle enhances physical performance in mice. NURR1 expression in skeletal muscle is also sufficient to prevent hyperglycemia and hepatic steatosis, by enhancing muscle glucose uptake and storage as glycogen. Furthermore, treatment of obese mice with putative NURR1 agonists increases energy expenditure, improves glucose tolerance, and confers a lean phenotype, mimicking the effects of exercise. These findings identify a key role for NURR1 in governance of skeletal muscle glucose metabolism, and reveal a transcriptional link between exercise and metabolism. Our findings also identify NURR1 agonists as possible exercise mimetics with the potential to ameliorate obesity and other metabolic abnormalities.exercise | Mediator complex | metabolic syndrome | nuclear receptor | obesity W hile the beneficial effects of exercise on metabolism and overall organismal health are well-known, much remains to be learned about the mechanistic basis of the benefits of physical activity and the systemic interactions among tissues and organs. Skeletal muscle accounts for ∼40% of body mass in healthy individuals, and represents the major site of glucose uptake and metabolism in the body (1, 2). During exercise, glycogen is metabolized in the liver to yield glucose, which is taken up by skeletal muscle to provide energy for contraction (3-5).Conversely, under conditions of caloric excess, glucose and fatty acids are directed to the liver, where energy is stored as triglycerides, causing hepatic steatosis, a growing health concern (6, 7). Uptake of glucose by skeletal muscle is mediated by GLUT4, the major glucose transporter in the sarcolemma (8-10). Exercise induces expression of GLUT4 and its translocation from intracellular stores to the sarcolemma (11). A variety of exerciseresponsive signal transduction pathways culminate in the nucleus to modulate the expression of GLUT4 and other metabolic genes (12). Key among the signal transducers in these pathways are AMPK and several calcium-sensitive kinases that regulate transcription by targeting class II histone deacetylases (HDACs), which relieves their repressive influence on MEF2 and other transcription factors (13-16). Integration of metabolic gene regulation also occurs through regulatory interactions between MEF2 and the nuclear coactivator PGC-1, which associates with PPAR and other nuclear receptors to enhance metabolic gene expression (17).Recently, we showed that MED13, a component of the Mediator complex, modulates systemic metabolism in skeletal muscle by suppressing the expression of Glut4 and other genes involved in glucose uptake and glycogen storage (18,19). Among a collection of genes up-regulated in skeletal...

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“…Chloroquine, for example, increases lysosomal volume (Chen et al, 2011), and either can or cannot increase intralysosomal pH (Poole and Ohkuma, 1981), thus resulting in an increased Acridine Orange R/GFIR (Liang et al, 2014;Shichiri et al, 2012) that does not reflect an increase in autophagy. Other biological effects, such as alterations in cell size, which are fairly common upon treatments that modulate autophagy, could be solved by considering R/GFIR rather than the red fluorescence.…”

Section: Discussionmentioning

confidence: 99%

Ratiometric analysis of acridine orange staining in the study of acidic organelles and autophagy

Thomé

Filippi-Chiela

Villodre

et al. 2016

Journal of Cell Science

191

207

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Acridine Orange is a cell-permeable green fluorophore that can be protonated and trapped in acidic vesicular organelles (AVOs). Its metachromatic shift to red fluorescence is concentration-dependent and, therefore, Acridine Orange fluoresces red in AVOs, such as autolysosomes. This makes Acridine Orange staining a quick, accessible and reliable method to assess the volume of AVOs, which increases upon autophagy induction. Here, we describe a ratiometric analysis of autophagy using Acridine Orange, considering the red-to-green fluorescence intensity ratio (R/GFIR) to quantify flow cytometry and fluorescence microscopy data of Acridine-Orangestained cells. This method measured with accuracy the increase in autophagy induced by starvation or rapamycin, and the reduction in autophagy produced by bafilomycin A1 or the knockdown of Beclin1 or ATG7. Results obtained with Acridine Orange, considering R/GFIR, correlated with the conversion of the unlipidated form of LC3 (LC3-I) into the lipidated form (LC3-II), SQSTM1 degradation and GFP-LC3 puncta formation, thus validating this assay to be used as an initial and quantitative method for evaluating the late step of autophagy in individual cells, complementing other methods.

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Suppression of autophagy by chloroquine sensitizes 5-fluorouracil-mediated cell death in gallbladder carcinoma cells

Cited by 66 publications

References 40 publications

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

The importance of epithelial-mesenchymal transition and autophagy in cancer drug resistance

NURR1 activation in skeletal muscle controls systemic energy homeostasis

Ratiometric analysis of acridine orange staining in the study of acidic organelles and autophagy

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