GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

Mukha, Anna; Kahya, Uğur; Linge, Annett; Chen, Oleg; Löck, Steffen; Lukiyanchuk, Vasyl; Richter, Susan; Alves, Tiago C.; Peitzsch, Mirko; Telychko, Vladyslav; Skvortsov, Sergej; Negro, G.; Aschenbrenner, Bertram; Skvortsova, Ira; Mirtschink, Peter; Lohaus, Fabian; Hölscher, Tobias; Neubauer, Hans; Rivandi, Mahdi; Labitzky, Vera; Lange, Tobias; Franken, A; Behrens, Bianca; Stoecklein, Nikolas H.; Toma, Marieta; Sommer, Ulrich; Zschaeck, Sebastian; Rehm, Maximilian; Eisenhofer, Graeme; Schwager, Christian; Abdollahi, Amir; Groeben, Christer; Kunz‐Schughart, Leoni A.; Baretton, Gustavo; Baumann, Michaël; Krause, Mechthild; Peitzsch, Claudia; Dubrovska, Anna

doi:10.7150/thno.58655

Cited by 102 publications

(111 citation statements)

References 87 publications

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“…Primary cultures were not further used past passage 5. The gene expression profiling and functional characterization of the primary cultures including clinical characteristics of enrolled patients was previously published (Mukha et al, 2021). The median age of included patients was determined as being 68 years [range: 62; 76], a median Gleason score of 7 [3 + 3; 5 + 5] and a median PSA level at diagnosis with 8.82 ng/mL [5.14; 38].…”

Section: Primary Prostate Culturesmentioning

confidence: 99%

Cellular plasticity upon proton irradiation determines tumor cell radiosensitivity

et al. 2022

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Section: Primary Prostate Culturesmentioning

confidence: 99%

Cellular plasticity upon proton irradiation determines tumor cell radiosensitivity

et al. 2022

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“…Our recent study demonstrated that prostate cancer cells and CSCs, in particular, are addicted to glutamine [ 1 ]. Glutamine is a non-essential amino acid that becomes conditionally essential for fast-proliferating tissues, including cancer.…”

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confidence: 99%

Targeting glutamine metabolism and autophagy: the combination for prostate cancer radiosensitization

2021

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Radiotherapy is one of the curative mainstays of prostate cancer; however, its efficacy is often diminished by tumor radioresistance. Depending on the stage of disease, tumors can relapse in approximately 50% of patients with prostate cancer after radiotherapy. Nevertheless, the mechanisms that drive tumor cell survival are not fully characterized, and reliable molecular prognostic markers of prostate cancer radioresistance are missing. Similar to other tumor entities, prostate cancer cells are heterogeneous in their capability to maintain tumor growth. The populations of cancer stem cells (CSCs) with self-renewal and differentiation properties are responsible for tumor development and recurrence after treatment. Eradication of these CSC populations is of utmost importance for efficient tumor cure. In a recently published study, we showed that prostate cancer cells could be radiosensitized by glutamine deprivation, resulting in DNA damage, oxidative stress, epigenetic modifications, and depletion of CSCs. Conversely, prostate cancer cells with resistance to glutamine depletion show an activation of ATG-mediated macroautophagy/autophagy as a survival strategy to withstand radiation-induced damage. Thus, a combination of targeting glutamine metabolism and autophagy blockade lead to more efficient prostate cancer radiosensitization.

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“…The authors showed that an increase in phosphoribosyl pyrophosphate amidotransferase (PPAT) and PPAT/GLS ratio is required to trigger nitrogen shift towards nucleotide biosynthesis in lung cancer and could be considered as a universal phenomenon in other cancer types apart from colorectal cancer [98]. Moreover, the authors further suggested, contrary to the previous observations, that GLS1 possesses antitumor effect rather than protumoral activity, which would call into question all previous reports showing, for instance, involvement of Gln in cancer cell redox homeostasis [117] or lipogenesis [56] and aspartate [108] metabolism. Thus, it would be interesting to investigate multiple tumors under various conditions and assess whether the tumor heterogeneity could explain the inconsistency between the recent report and previous studies.…”

Section: Glutamine Synthesis Glulmentioning

confidence: 76%

Advancing Cancer Treatment by Targeting Glutamine Metabolism—A Roadmap

Halama

Suhre

2022

Cancers

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Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications.

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GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy

Cited by 102 publications

References 87 publications

Cellular plasticity upon proton irradiation determines tumor cell radiosensitivity

Cellular plasticity upon proton irradiation determines tumor cell radiosensitivity

Targeting glutamine metabolism and autophagy: the combination for prostate cancer radiosensitization

Advancing Cancer Treatment by Targeting Glutamine Metabolism—A Roadmap

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