Glutamine depletion and glucose depletion trigger growth inhibition via distinctive gene expression reprogramming

Qie, Shuo; Liang, Dongming; Yin, Chengqian; Gu, Wen; Meng, Meng; Wang, Chenguang; Sang, Nianli

doi:10.4161/cc.21944

Cited by 48 publications

(47 citation statements)

References 43 publications

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“…How radiation activates HIF‐1 remains unclear; it has been reported that radiation activates AMPK and the ATF4 pathway [Fels and Koumenis, ; Lee et al, ; Cao and Wan, ; Sanli et al, , ; Zhang et al, ; Zannella et al, ; Kim et al, ], and overexpression of STC2, an ATF4 target, positively correlates to radiation resistance [Smith et al, ; Lin et al, ]. It is interesting to note that an intriguing similarity exists between the radiation‐triggered and the nutrient insufficiency‐triggered cellular responses: both induce cell cycle inhibition, activation of AMPK, activation of ATF4 pathways [Meng et al, ; Qie et al, ; Davie et al, ], and most importnatly, activation of HIF‐1. However, a mechanistic link among those responses remains unclear.…”

Section: Proliferative Signaling Pathways Activate Hif‐1 By Acceleratmentioning

confidence: 99%

Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells

Chen

Sang

2015

J. Cell. Biochem.

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HIF-1 activation has been well known as an adaptive strategy to hypoxia. Recently it became clear that hypoxia was often accompanied by insufficient supply of glucose or amino acids as a common result of poor circulation that frequently occurs in solid tumors and ischemic lesions, creating a mixed nutrient insufficiency. In response to nutrient insufficiency, stressed cells elicit survival strategies including activation of AMPK and HIF-1 to cope with the stress. Particularly, in solid tumors, HIF-1 promotes cell survival and migration, stimulates angiogenesis, and induces resistance to radiation and chemotherapy. Interestingly, radiation and some chemotherapeutics are reported to trigger the activation of AMPK. Here we discuss the recent advances that may potentially link the stress responsive mechanisms including AMPK activation, ATF4 activation and the enhancement of Hsp70/Hsp90 function to HIF-1 activation. Potential implication and application of the stress-facilitated HIF-1 activation in solid tumors and ischemic disorders will be discussed. A better understanding of HIF-1 activation in cells exposed to stresses is expected to facilitate the design of therapeutic approaches that specifically modulate cell survival strategy.

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Section: Proliferative Signaling Pathways Activate Hif‐1 By Acceleratmentioning

confidence: 99%

Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells

Chen

Sang

2015

J. Cell. Biochem.

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“…This disrupts tumour metabolism-dependent antioxidant defences (Trachootham et al , 2009), thereby elevating cytotoxic reactive oxygen species (ROS) (Kim et al , 2008; Aykin-Burns et al , 2009). Additionally, glycolysis inhibitors impair energy-dependent DNA repair and cellular recovery processes (Dwarakanath, 2009), cause cell cycle arrest (Qie et al , 2012), and initiate apoptosis by inhibiting antiapoptotic Bcl-2 family members (Ravagnan et al , 1999; Zagorodna et al , 2012). Finally, glycolysis inhibitors downregulate ABC transporters, thereby overcoming multidrug resistance (Wartenberg et al , 2010; Nakano et al , 2011).…”

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confidence: 99%

Targeting tumour energy metabolism potentiates the cytotoxicity of 5-aminolevulinic acid photodynamic therapy

et al. 2013

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Background:Cancerous cells usually exhibit increased aerobic glycolysis, compared with normal tissue (the Warburg effect), making this pathway an attractive therapeutic target.Methods:Cell viability, cell number, clonogenic assay, reactive oxygen (ROS), ATP, and apoptosis were assayed in MCF-7 tumour cells and corresponding primary human mammary epithelial cells (HMEC).Results:Combining the glycolysis inhibitors 2-deoxyglucose (2DG; 180 mM) or lonidamine (300 μM) with 10 J cm−2 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) increases MCF-7 cytotoxicity (by 3.5-fold to 70% death after 24 h, and by 10-fold in 9-day clonogenic assays). However, glycolysis inhibition only slightly increases HMEC PDT cytotoxicity (between two-fold and three-fold to a maximum of 9% death after 24 h). The potentiation of PDT cytotoxicity only occurred if the glycolysis inhibitors were added after ALA incubation, as they inhibited intracellular accumulation of photosensitiser if coincubated with ALA.Conclusion:As 2DG and lonidamine are already used as cancer chemotherapeutic agents, our results are directly translatable to combination therapies with existing topical PDT.

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“…14–16 Deprivation of amino acids results in growth inhibition or death of tumor cells by the modulation of various signaling cascades. 6–9,17,18 …”

Section: Introductionmentioning

confidence: 99%

“…Currently, there is a resurgence of interest in enzyme-mediated amino acid deprivation as a new therapeutic approach for cancer treatment. 6,7,21,22 For example, arginine depletion can inhibit tumor cell proliferation and induce cell death pathways. Here we endeavor to provide a basic understanding of the roles of arginine in normal and tumor cell with emphasis on current knowledge and developments in the application of enzyme-mediated arginine-depriving therapy as a potential anti-cancer approach.…”

Section: Introductionmentioning

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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Glutamine depletion and glucose depletion trigger growth inhibition via distinctive gene expression reprogramming

Cited by 48 publications

References 43 publications

Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells

Hypoxia-Inducible Factor-1: A Critical Player in the Survival Strategy of Stressed Cells

Targeting tumour energy metabolism potentiates the cytotoxicity of 5-aminolevulinic acid photodynamic therapy

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

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