Targeting asparagine and autophagy for pulmonary adenocarcinoma therapy

Zhang, Boyang; Fan, Jiajun; Zhang, Xu-Yao; Shen, Weitao; Cao, Ziping; Yang, Ping; Xu, Zhongyuan; Ju, Dianwen

doi:10.1007/s00253-016-7640-3

Cited by 26 publications

(19 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Asparaginase has been approved for treatment of childhood ALL by FDA for more than 40 years. Recent studies revealed that asparaginase could be used as a chemotherapeutic agent against not only ALL but also other types of leukemia and several malignant solid cancers [ 18 – 26 ]. In addition, several literature has reported the anti-tumor effect of asparaginase on glioblastoma [ 10 , 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, L-asparagine is an essential amino acid for cancer cell growth, and asparagine depletion has become one of the most promising strategies for cancer therapy [ 15 – 17 ]. Except for being proved for treatment of ALL, asparaginase is also reported to be effective in treatment of other kinds of leukemia including non-Hodgkin’s lymphoma [ 18 ], acute myelocytic leukemia (AML) [ 19 , 20 ], chronic myelocytic leukemia (CML) [ 21 ], chronic lymphocytic leukemia (CLL) and several malignant solid cancers such as melanosarcoma [ 22 , 23 ], ovarian cancer [ 24 , 25 ] and pulmonary adenocarcinoma (ADCA) [ 26 ]. Recent study reported that depletion of asparagine by asparaginase sensitized GBM cells to apoptosis in vitro and in vivo [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

“…Cytoprotective autophagy could be induced by chemotherapeutics such as temozolomide [ 38 – 40 ], Vismodegib [ 41 ] and cisplatin [ 42 ], and depletion of autophagy could prominently enhance the cytotoxicity of these chemotherapeutics. Importantly, in amino acid deprivation therapy for hematologic and solid malignancies using asparaginase and arginase, autophagy can initiate therapy-resistance [ 21 , 26 , 28 , 29 ]. Therefore, we highly speculated that asparaginase could trigger autophagy in GBM cells, and suppression of autophagy could potentiate the anti-tumor effect of asparagine depletion on glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

Chen

Fan

et al. 2017

Oncotarget

Self Cite

View full text Add to dashboard Cite

Asparaginase has been reported to be effective in the treatment of various leukemia and several malignant solid cancers. However, the anti-tumor effect of asparaginase is always restricted due to complicated mechanisms. Herein, we investigated the mechanisms of how glioblastoma resisted asparaginase treatment and reported a novel approach to enhance the anti-glioblastoma effect of asparaginase. We found that asparaginase could induce growth inhibition and caspase-dependent apoptosis in U87MG/U251MG glioblastoma cells. Meanwhile, autophagy was activated as indicated by autophagosomes formation and upregulated expression of LC3-II. Importantly, abolishing autophagy using chloroquine (CQ) and LY294002 enhanced the cytotoxicity and apoptosis induced by asparaginase in U87MG/U251MG cells. Further study proved that Akt/mTOR and Erk signaling pathways participated in autophagy induction, while reactive oxygen species (ROS) served as an intracellular regulator for both cytotoxicity and autophagy in asparaginase-treated U87MG/U251MG cells. Moreover, combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model.Taken together, our results demonstrated that inhibition of autophagy potentiated the anti-tumor effect of asparagine depletion on glioblastoma, indicating that targeting autophagy and asparagine could be a potential approach for glioblastoma treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

Chen

Fan

et al. 2017

Oncotarget

Self Cite

View full text Add to dashboard Cite

show abstract

“…41 Samples were examined with a JEM 1400 transmission electron microscope (JEOL, Inc., Peabody, MA, USA) at 80 kV.…”

Section: Methodsmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Since asparagine is a downstream metabolite of glutamine, combined inhibition of GLS1 with asparagine deprivation is synthetically lethal for solid tumor cells (Li et al , ). Notably, asparaginase treatment is also effective for solid tumors, when combined with inhibition of autophagy (Zhang et al , ; Li et al , ).…”

Section: Introductionmentioning

confidence: 99%

Role of glutamine and interlinked asparagine metabolism in vessel formation

et al. 2017

View full text Add to dashboard Cite

Endothelial cell (EC) metabolism is emerging as a regulator of angiogenesis, but the precise role of glutamine metabolism in ECs is unknown. Here, we show that depriving ECs of glutamine or inhibiting glutaminase 1 (GLS1) caused vessel sprouting defects due to impaired proliferation and migration, and reduced pathological ocular angiogenesis. Inhibition of glutamine metabolism in ECs did not cause energy distress, but impaired tricarboxylic acid (TCA) cycle anaplerosis, macromolecule production, and redox homeostasis. Only the combination of TCA cycle replenishment plus asparagine supplementation restored the metabolic aberrations and proliferation defect caused by glutamine deprivation. Mechanistically, glutamine provided nitrogen for asparagine synthesis to sustain cellular homeostasis. While ECs can take up asparagine, silencing asparagine synthetase (ASNS, which converts glutamine-derived nitrogen and aspartate to asparagine) impaired EC sprouting even in the presence of glutamine and asparagine. Asparagine further proved crucial in glutamine-deprived ECs to restore protein synthesis, suppress ER stress, and reactivate mTOR signaling. These findings reveal a novel link between endothelial glutamine and asparagine metabolism in vessel sprouting.

show abstract

Targeting asparagine and autophagy for pulmonary adenocarcinoma therapy

Cited by 26 publications

References 50 publications

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

Autophagy suppression potentiates the anti-glioblastoma effect of asparaginase in vitro and in vivo

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

Role of glutamine and interlinked asparagine metabolism in vessel formation

Contact Info

Product

Resources

About