Blocking autophagy enhanced cytotoxicity induced by recombinant human arginase in triple-negative breast cancer cells

Z, Wang; Shi, Xiaowen; Li, Yubin; Fan, Jia; Zeng, Xian; Xian, Zongshu; Sun, Yun; Wang, S; Song, Ping; Zhao, Song; Hu, Haifeng; Ju, Dianwen

doi:10.1038/cddis.2014.503

Cited by 59 publications

(53 citation statements)

References 38 publications

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“…31 Meanwhile, rhArg has been demonstrated to be significant cytotoxicity in triple-negative breast cancers and laryngeal squamous cell carcinoma. 9, 10 However, it has never been reported whether NSCLC cells were sensitive to rhArg treatment.…”

Section: Discussionmentioning

confidence: 99%

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A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor

Shen

Zhang

et al. 2017

Cell Death Dis

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Recombinant human arginase (rhArg), an enzyme capable of depleting arginine, has been shown to be an effective therapeutic approach for various cancers. Non-small-cell lung cancer (NSCLC), a histological subtype of pulmonary carcinoma, has a high rate of morbidity and mortality in the world. Thus, the need for novel and more effective treatment is urgent. In this study, it is the first time to report that rhArg could induce significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells. Subsequently, our research revealed that rhArg dramatically stimulated autophagic response in NSCLC cells, which was proved by the formation and accumulation of autophagosomes and the conversion of microtubule-associated protein light chain 3 (LC3) from LC3-I to LC3-II. Furthermore, blocking autophagy by chloroquine or LY294002 remarkably enhanced rhArg-induced cytotoxicity and caspase-dependent apoptosis, suggesting that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells. Further experiments showed that two signaling pathways including the Akt/mTOR and extracellular signal-regulated kinase pathway, and mitochondrial-derived reactive oxygen species (ROS) production were involved in rhArg-induced autophagy and apoptosis. Meanwhile, N-acetyl-L-cysteine, a common antioxidant, was employed to scavenge ROS, and we detected that it could significantly block rhArg-induced autophagy and cytotoxicity, indicating that ROS played a vital role in arginine degradation therapy. Besides, xenograft experiment showed that combination with autophagy inhibitor potentiated the anti-tumor efficacy of rhArg in vivo. Therefore, these results provided a novel prospect and viewpoint that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells, and treatment with rhArg alone or combined with autophagy inhibitor could be a novel and promising therapeutic approach for NSCLC in vivo and in vitro.

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Section: Discussionmentioning

confidence: 99%

“…9 It has been widely reported that depleting amino acids could stimulate autophagy, in response to nutrition stress. 12 Mounts of studies indicated that autophagy played a cytoprotective role in pathogenesis process and antitumor therapy.…”

mentioning

confidence: 99%

A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor

Shen

Zhang

et al. 2017

Cell Death Dis

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“…Our results suggest that peiminine induces G1/G0 phase arrest by increasing the expression of p21 and p27 and decreasing the expression of cyclin D1, CDK2 and CDK4. Autophagy is a double-edged sword in tumour progression and treatment: it can either facilitate cancer survival under metabolic stress or induce autophagic tumour cell death [35,36]. Mounting evidence accumulated in recent years suggests that inhibition of autophagy can reduce the treatment resistance of chemotherapy and radiotherapy in various types of cancers [37,38], which is also the case in GBM treatment [39,40].…”

Section: Discussionmentioning

confidence: 99%

Peiminine Inhibits Glioblastoma in Vitro and in Vivo Through Cell Cycle Arrest and Autophagic Flux Blocking

Zhao¹,

Shen²,

Zheng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Glioblastoma multiforme (GBM) is the most devastating and widespread primary central nervous system tumour in adults, with poor survival rate and high mortality rates. Existing treatments do not provide substantial benefits to patients; therefore, novel treatment strategies are required. Peiminine, a natural bioactive compound extracted from the traditional Chinese medicine Fritillaria thunbergii, has many pharmacological effects, especially anticancer activities. However, its anticancer effects on GBM and the underlying mechanism have not been demonstrated. This study was conducted to investigate the potential antitumour effects of peiminine in human GBM cells and to explore the related molecular signalling mechanisms in vitro and in vivo Methods: Cell viability and proliferation were detected with MTT and colony formation assays. Morphological changes associated with autophagy were assessed by transmission electron microscopy (TEM). The cell cycle rate was measured by flow cytometry. To detect changes in related genes and signalling pathways in vitro and in vivo, RNA-seq, Western blotting and immunohistochemical analyses were employed. Results: Peiminine significantly inhibited the proliferation and colony formation of GBM cells and resulted in changes in many tumour-related genes and transcriptional products. The potential anti-GBM role of peiminine might involve cell cycle arrest and autophagic flux blocking via changes in expression of the cyclin D1/CDK network, p62 and LC3. Changes in Changes in flow cytometry results and TEM findings were also observed. Molecular alterations included downregulation of the expression of not only phospho-Akt and phospho-GSK3β but also phospho-AMPK and phospho-ULK1. Furthermore, overexpression of AKT and inhibition of AKT reversed and augmented peiminine-induced cell cycle arrest in GBM cells, respectively. The cellular activation of AMPK reversed the changes in the levels of protein markers of autophagic flux. These results demonstrated that peiminine mediates cell cycle arrest by suppressing AktGSk3β signalling and blocks autophagic flux by depressing AMPK-ULK1 signalling in GBM cells. Finally, peiminine inhibited the growth of U251 gliomas in vivo. Conclusion: Peiminine inhibits glioblastoma in vitro and in vivo via arresting the cell cycle and blocking autophagic flux, suggesting new avenues for GBM therapy.

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“…143 Inhibition of autophagy in amino acid deficient conditions induces tumor cell death, mainly because of further exacerbation of energy dearth. 167,168 Also, longer persistence of autophagy is proposed to eventually lead the activation of caspase-dependent cell death pathways, as autophagy and apoptotic cell death pathways are interconnected and also share some common pathways through the induction of the membrane permeability transitions. 169–171 Induction of apoptotic pathways is another consequence of arginine depletion and anti-tumor mechanism of arginase I-mediated arginine deprivation.…”

Section: Arginasementioning

confidence: 99%

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

et al. 2016

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Arginine, one among the 20 most common natural amino acids, has a pivotal role in cellular physiology as it is being involved in numerous cellular metabolic and signaling pathways. Dependence on arginine is diverse for both tumor and normal cells. Because of decreased expression of argininosuccinate synthetase and/or ornithine transcarbamoylase, several types of tumor are auxotrophic for arginine. Deprivation of arginine exploits a significant vulnerability of these tumor cells and leads to their rapid demise. Hence, enzyme-mediated arginine depletion is a potential strategy for the selective destruction of tumor cells. Arginase, arginine deiminase and arginine decarboxylase are potential enzymes that may be used for arginine deprivation therapy. These arginine catabolizing enzymes not only reduce tumor growth but also make them susceptible to concomitantly administered anti-cancer therapeutics. Most of these enzymes are currently under clinical investigations and if successful will potentially be advanced as anti-cancer modalities.

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Blocking autophagy enhanced cytotoxicity induced by recombinant human arginase in triple-negative breast cancer cells

Cited by 59 publications

References 38 publications

A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor

A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor

Peiminine Inhibits Glioblastoma in Vitro and in Vivo Through Cell Cycle Arrest and Autophagic Flux Blocking

Arginine dependence of tumor cells: targeting a chink in cancer’s armor

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