Int J Biol Sci 2023; 19(3):772-788. doi:10.7150/ijbs.78948 This issue Cite

Research Paper

Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation

Man-man Chen1,3, Wei Guo1,3, Si-meng Chen1, Xiao-zhen Guo2, Lan Xu1, Xiao-yu Ma1,3, Yu-xiang Wang1, Cen Xie2,3, Ling-hua Meng1,3✉

1. Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
3. University of Chinese Academy of Sciences, Beijing 100049, China.

Citation:
Chen Mm, Guo W, Chen Sm, Guo Xz, Xu L, Ma Xy, Wang Yx, Xie C, Meng Lh. Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation. Int J Biol Sci 2023; 19(3):772-788. doi:10.7150/ijbs.78948. https://www.ijbs.com/v19p0772.htm
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Abstract

Graphic abstract

Xanthine dehydrogenase (XDH) is the rate-limiting enzyme in purine catabolism by converting hypoxanthine to xanthine and xanthine to uric acid. The altered expression and activity of XDH are associated with the development and prognosis of multiple types of cancer, while its role in lung adenocarcinoma (LUAD) remains unknown. Herein, we demonstrated that XDH was highly expressed in LUAD and was significantly correlated with poor prognosis. Though inhibition of XDH displayed moderate effect on the viability of LUAD cells cultured in the complete medium, it significantly attenuated the survival of starved cells. Similar results were obtained in XDH-knockout cells. Nucleosides supplementation rescued the survival of starved LUAD cells upon XDH inhibition, while inhibition of purine nucleoside phosphorylase abrogated the process, indicating that nucleoside degradation is required for the XDH-mediated survival of LUAD cells. Accordingly, metabolic flux revealed that ribose derived from nucleoside fueled key carbon metabolic pathways to sustain the survival of starved LUAD cells. Mechanistically, down-regulation of XDH suppressed unfolded protein response (UPR) and autophagic flux in starved LUAD cells. Inhibition of XDH decreased the level of amino acids produced by autophagic degradation, which was accompanied with down-regulation of mTORC1 signaling. Supplementation of amino acids including glutamine or glutamate rescued the survival of starved LUAD cells upon knockout or inhibition of XDH. Finally, XDH inhibitors potentiated the anti-cancer activity of 2-deoxy-D-glucose that induced UPR and/or autophagy in vitro and in vivo. In summary, XDH plays a crucial role in the survival of starved LUAD cells and targeting XDH may improve the efficacy of drugs that induce UPR and autophagy in the therapy of LUAD.

Keywords: Xanthine dehydrogenase, nucleoside degradation, cell survival, UPR, autophagy, LUAD


Citation styles

APA
Chen, M.m., Guo, W., Chen, S.m., Guo, X.z., Xu, L., Ma, X.y., Wang, Y.x., Xie, C., Meng, L.h. (2023). Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation. International Journal of Biological Sciences, 19(3), 772-788. https://doi.org/10.7150/ijbs.78948.

ACS
Chen, M.m.; Guo, W.; Chen, S.m.; Guo, X.z.; Xu, L.; Ma, X.y.; Wang, Y.x.; Xie, C.; Meng, L.h. Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation. Int. J. Biol. Sci. 2023, 19 (3), 772-788. DOI: 10.7150/ijbs.78948.

NLM
Chen Mm, Guo W, Chen Sm, Guo Xz, Xu L, Ma Xy, Wang Yx, Xie C, Meng Lh. Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation. Int J Biol Sci 2023; 19(3):772-788. doi:10.7150/ijbs.78948. https://www.ijbs.com/v19p0772.htm

CSE
Chen Mm, Guo W, Chen Sm, Guo Xz, Xu L, Ma Xy, Wang Yx, Xie C, Meng Lh. 2023. Xanthine dehydrogenase rewires metabolism and the survival of nutrient deprived lung adenocarcinoma cells by facilitating UPR and autophagic degradation. Int J Biol Sci. 19(3):772-788.

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