Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy

Liu, Huailei; Zhang, Weiguang; Wang, Kaikai; Wang, Xiaoxiong; Yin, Fei; Li, Chenguang; Wang, Chunlei; Zhao, Boxian; Chen, Zhong; Zhang, Jiakang; Peng, Fei; Bi, Yunke; Shen, Chen; Hou, Xu; Zhang, Daming; Liu, Yaohua; Ai, Jing; Zhao, Shen

doi:10.1016/j.toxlet.2014.11.011

Cited by 44 publications

(48 citation statements)

References 35 publications

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“…Met or Cys deprivation alone already resulted in decreased proliferation of cells of the glioma cell lines U87 and U251 (Liu et al 2015). Double deprivation had a synergistic effect.…”

Section: Glutamate and α-Ketoglutarate In Glioma Metabolismmentioning

confidence: 99%

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Glutamate and α-ketoglutarate: key players in glioma metabolism

Maus

Peters

2016

Amino Acids

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Glioblastoma multiforme (GBM), or grade IV astrocytoma, is the most common type of primary brain tumor. It has a devastating prognosis with a 2-year-overall survival rate of only 26 % after standard treatment, which includes surgery, radiation, and adjuvant chemotherapy with temozolomide. Also lower grade gliomas are difficult to treat, because they diffusely spread into the brain, where extensive removal of tissue is critical. Better understanding of the cancer’s biology is a key for the development of more effective therapy approaches. The discovery of isocitrate dehydrogenase (IDH) mutations in leukemia and glioma drew attention to specific metabolic aberrations in IDH-mutant gliomas. In the center of the metabolic alterations is α-ketoglutarate (αKG), an intermediate metabolite in the tricarboxylic acid (TCA) cycle, and the associated amino acid glutamate (Glu). This article highlights the role of these metabolites in glioma energy and lipid production and indicates possible weak spots of IDH-mutant and IDH-wt gliomas.

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“…Met or Cys deprivation alone already resulted in decreased proliferation of cells of the glioma cell lines U87 and U251 (Liu et al 2015). Double deprivation had a synergistic effect.…”

Section: Glutamate and α-Ketoglutarate In Glioma Metabolismmentioning

confidence: 99%

“…Also the induction of ROS can induce autophagy in cancer cells (reviewed by Bellot et al 2013). Liu et al (2015) studied the effects of double deprivation on autophagy. Met–Cys double deprivation led to an increased abundance of the autophagy-related protein LC3-II and autophagosomes.…”

Section: Glutamate and α-Ketoglutarate In Glioma Metabolismmentioning

confidence: 99%

Glutamate and α-ketoglutarate: key players in glioma metabolism

Maus

Peters

2016

Amino Acids

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“…Methionine is absolutely required for protein synthesis, since every new protein sequence starts with a methionine residue [24-26]. Note that mammosphere formation was dramatically inhibited by methionine deprivation (Figure 7), which mimics the positive effects of caloric restriction in cultured cells.…”

Section: Resultsmentioning

confidence: 99%

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Lamb¹,

Harrison

Smith

et al. 2015

Oncotarget

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We have used an unbiased proteomic profiling strategy to identify new potential therapeutic targets in tumor-initiating cells (TICs), a.k.a., cancer stem cells (CSCs). Towards this end, the proteomes of mammospheres from two breast cancer cell lines were directly compared to attached monolayer cells. This allowed us to identify proteins that were highly over-expressed in CSCs and/or progenitor cells. We focused on ribosomal proteins and protein folding chaperones, since they were markedly over-expressed in mammospheres. Overall, we identified >80 molecules specifically associated with protein synthesis that were commonly upregulated in mammospheres. Most of these proteins were also transcriptionally upregulated in human breast cancer cells in vivo, providing evidence for their potential clinical relevance. As such, increased mRNA translation could provide a novel mechanism for enhancing the proliferative clonal expansion of TICs. The proteomic findings were functionally validated using known inhibitors of protein synthesis, via three independent approaches. For example, puromycin (which mimics the structure of tRNAs and competitively inhibits protein synthesis) preferentially targeted CSCs in both mammospheres and monolayer cultures, and was ~10-fold more potent for eradicating TICs, than “bulk” cancer cells. In addition, rapamycin, which inhibits mTOR and hence protein synthesis, was very effective at reducing mammosphere formation, at nanomolar concentrations. Finally, mammosphere formation was also markedly inhibited by methionine restriction, which mimics the positive effects of caloric restriction in cultured cells. Remarkably, mammosphere formation was >18-fold more sensitive to methionine restriction and replacement, as directly compared to monolayer cell proliferation. Methionine is absolutely required for protein synthesis, since every protein sequence starts with a methionine residue. Thus, the proliferation and survival of CSCs is very sensitive to the inhibition of protein synthesis, using multiple independent approaches. Our findings have important clinical implications, since they may also explain the positive therapeutic effects of PI3-kinase inhibitors and AKT inhibitors, as they ultimately converge on mTOR signaling and would block protein synthesis. We conclude that inhibition of mRNA translation by pharmacological or protein/methionine restriction may be effective strategies for eliminating TICs. Our data also indicate a novel mechanism by which caloric/protein restriction may reduce tumor growth, by targeting protein synthesis in anabolic tumor-initiating cancer cells.

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“…Over the past 40 years, it has become increasingly clear that tumor cells exhibit specific amino acid dependency, and cells from different tumors were shown to die quickly in vitro following arginine, cysteine, or glutamine deprivation, while normal cells survived (Liu et al 2015). p53-deficient tumors are vulnerable to serine/glycine starvation (Maddocks et al 2013), although current therapies do not fully exploit this major difference between cancer cells and nonneoplastic cells.…”

Section: Discussionmentioning

confidence: 99%

TAp73 is a marker of glutamine addiction in medulloblastoma

et al. 2017

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Medulloblastoma is the most common solid primary brain tumor in children. Remarkable advancements in the understanding of the genetic and epigenetic basis of these tumors have informed their recent molecular classification. However, the genotype/phenotype correlation of the subgroups remains largely uncharacterized. In particular, the metabolic phenotype is of great interest because of its druggability, which could lead to the development of novel and more tailored therapies for a subset of medulloblastoma. p73 plays a critical role in a range of cellular metabolic processes. We show overexpression of p73 in a proportion of non-WNT medulloblastoma. In these tumors, p73 sustains cell growth and proliferation via regulation of glutamine metabolism. We validated our results in a xenograft model in which we observed an increase in survival time in mice on a glutamine restriction diet. Notably, glutamine starvation has a synergistic effect with cisplatin, a component of the current medulloblastoma chemotherapy. These findings raise the possibility that glutamine depletion can be used as an adjuvant treatment for p73-expressing medulloblastoma.

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Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy

Cited by 44 publications

References 35 publications

Glutamate and α-ketoglutarate: key players in glioma metabolism

Glutamate and α-ketoglutarate: key players in glioma metabolism

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

TAp73 is a marker of glutamine addiction in medulloblastoma

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