Abstract
Radiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Here, we found that radioresistant PCa cells and prostate cancer stem cells (CSCs) have a high glutamine demand. Glutaminase (GLS)-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as glutaminase (GLS) and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (α-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populations in vivo and reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.
Competing Interest Statement
In the past 5 years, Dr. Michael Baumann attended an advisory board meeting of MERCK KGaA (Darmstadt), for which the University of Dresden received a travel grant. He further received funding for his research projects and for educational grants to the University of Dresden by Teutopharma GmbH (2011-2015), IBA (2016), Bayer AG (2016-2018), Merck KGaA (2014-open), Medipan GmbH (2014-2018). He is on the supervisory board of HI-STEM gGmbH (Heidelberg) for the German Cancer Research Center (DKFZ, Heidelberg) and also member of the supervisory body of the Charite University Hospital, Berlin. As former chair of OncoRay (Dresden) and present CEO and Scientific Chair of the German Cancer Research Center (DKFZ, Heidelberg), he has been or is still responsible for collaborations with a multitude of companies and institutions, worldwide. In this capacity, he discussed potential projects with and has signed/signs contracts for his institute(s) and for the staff for research funding and/or collaborations with industry and academia, worldwide, including but not limited to pharmaceutical corporations like Bayer, Boehringer Ingelheim, Bosch, Roche and other corporations like Siemens, IBA, Varian, Elekta, Bruker and others. In this role, he was/is further responsible for commercial technology transfer activities of his institute(s), including the DKFZ-PSMA617 related patent portfolio [WO2015055318 (A1), ANTIGEN (PSMA)] and similar IP portfolios. Dr. Baumann confirms that to the best of his knowledge none of the above funding sources was involved in the preparation of this paper. In the past 5 years, Dr. Mechthild Krause received funding for her research projects by IBA (2016), Merck KGaA (2014-2018 for preclinical study; 2018-2020 for clinical study), Medipan GmbH (2014-2018). In the past 5 years, Dr. Krause, Dr. Linge and Dr. Lock have been involved in an ongoing publicly funded (German Federal Ministry of Education and Research) project with the companies Medipan, Attomol GmbH, GA Generic Assays GmbH, Gesellschaft fur medizinische und wissenschaftliche genetische Analysen, Lipotype GmbH and PolyAn GmbH (2019-2021). For the present manuscript, none of the above mentioned funding sources were involved. Other co-authors declare that they have no conflict of interest.
Standard abbreviations
- ALDH
- aldehyde dehydrogenase
- ALKBH
- Alkylated DNA Repair Protein AlkB Homolog family
- α-KG
- alpha-ketoglutarate
- ATG5
- autophagy related 5
- BPH
- benign prostate hyperplasia
- CSC
- cancer stem cell
- DDR
- DNA damage response
- Gln
- glutamine
- GLS
- glutaminase
- Glu
- glutamate
- GSH
- reduced glutathione
- GSSG
- oxidized glutathione
- LC3B
- Microtubule-associated proteins 1 light chain 3B
- OCR
- oxygen consumption rate
- PCa
- prostate cancer
- PDPC
- patient-derived primary cell cultures
- PSA
- prostate-specific antigen
- ROS
- reactive oxygen species
- RR
- radioresinance
- TCA cycle
- tricarboxylic acid cycle
- TCGA
- The Cancer Genome Atlas
- OXPHOS
- oxidative phosphorylation