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We have previously shown that the radioresistant prostate cancer (PCa) and PCa stem cells (CSCs) had increased glutamine (Gln) requirement (1). Gln conduces to energy production in the TCA cycle to sustain the redox state and tumor epigenetic resetting. Inhibition of the glutaminase-driven Gln catabolism set the ground for CSC depletion and tumor radiosensitization (1). Moreover, we demonstrated that autophagy is utilized by hormone-naive cells like LNCaP as a prosurvival strategy to cope with the Gln depletion (1, 2). Despite our previous study aiming to decipher mechanisms that link Gln metabolism and PCa radioresistance, we sought to explain the role of Gln transporters (GTs) in PCa development and radioresistance as it is not well understood and warrant further investigation. Understanding the role of GTs may provide better approaches for individualized treatment regimens to overcome PCa radioresistance (3). Thus, we hypothesized that targeting GTs may yield novel and efficient strategies for PCa radiosensitization. As a result of in-silico analyses, we focused on the solute carrier (SLC) group of membrane GTs, namely SLC1A5, SLC7A5, and SLC38A1. 

Differential expression of GTs in previously established parental and radioresistant DU145 and LNCaP PCa sublines is determined using global gene expression profiling and qRT-PCR (4). Mining of publicly available patient datasets validated the clinical relevance of the identified GT. To evaluate the role of GTs on PCa radiosensitization, colony formation and sphere formation assays using PC3, DU145, and LNCaP cells with siRNA-mediated knockdown of GTs has been performed.

Depletion of our candidates radiosensitizes PCa cell lines. Besides, reduced spherogenicity of DU145 but not LNCaP cells was observed after GTs depletion. These results are consistent with our published data showing that LNCaP cells use autophagy as a prosurvival mechanism upon disruption of Gln metabolism, which may also explain the unaltered spherogenicity of LNCaP cells upon depletion of GTs (1, 2). Unlike DU145 cells, which do not express ATG5 and do not show canonical autophagy, LNCaP cells are not solely dependent on the exogenous Gln as they can use autophagy to survive (5). Additionally, we observed statistically significant increased expression of GTs in DU145 cells compared to LNCaP cells upon Gln starvation, which may recapitulate dependency of DU145 cells on Gln for survival.

Targeting SLC1A5, SLC7A5, and SLC38A1 might offer a promising approach to radiosensitize PCa cells. Further studies to evaluate these GTs in clinical specimens by IHC to validate them as prospective biomarkers and in animal studies by their pharmacological inhibition may elucidate their potential as a therapeutic target for PCa radiosensitization.

References

1- Mukha, A. & Kahya, U. et al. Theranostics 2021

2- Mukha, A. et al. Autophagy 2021

3- Kahya, U. et al. Cancers 2021

4- Cojoc, M. et al. Cancer Res 2015

5- Peitzsch, C. Int J Radiat Biol 2014