Glutamine addiction activates polyglutamine-based nanocarriers delivering therapeutic siRNAs to orthotopic lung tumor mediated by glutamine transporter SLC1A5

Biomaterials
Cuifeng WangMin Feng

Abstract

Many human cancer cells exhibit an oncogenetic-driven addiction to glutamine (Gln) as rapidly proliferating cancer cells consume Gln at a dramatically increased rate compared to normal cells. Tumor cells, therefore, compete with host cells for Gln, which causes Gln to flux from normal tissues to the tumor. We have developed and characterized a Gln macromolecular analog polyglutamine (PGS) for the delivery of gene regulators, such as siRNAs, in our previous works. Here, we hypothesize that PGS can utilize the Gln transporter SLC1A5 to specifically deliver therapeutic compounds to Gln-addicted cancer cells. Compared to human lung fibroblast HLF cells, cisplatin-resistant human lung adenocarcinoma A549/DDP cells significantly overexpress SLC1A5, which has a high binding affinity to PGS, as confirmed through molecular docking analysis. Due to the differences in Gln metabolism between malignant and normal cells, PGS/siRNA complexes were remarkably increased in cancer cells, especially when cells were deprived of Gln, which mirrors the conditions that are commonly found in a tumor microenvironment. Furthermore, we identified that chemical and genetic inhibition of Gln transporter SLC1A5 reduced the cellular internalization of PGS/siR...Continue Reading

Citations

May 17, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Trevor W Hambley
Jan 7, 2021·Cancers·Uğur KahyaAnna Dubrovska
Feb 27, 2021·Molecular Cancer Therapeutics·Yongmei FengZe'ev A Ronai
Jul 13, 2021·Frontiers in Molecular Biosciences·Lude WangJianlie Yuan

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