Antagonizing Glutamine Bioavailability Promotes Radiation Sensitivity in Prostate Cancer

Abstract

Nearly half of localized prostate cancer (PCa) patients given radiation therapy develop recurrence. Here, we identified glutamine as a key player in mediating the radio-sensitivity of PCa. Glutamine transporters and glutaminase are upregulated by radiation therapy of PCa cells, but respective inhibitors were ineffective in radio-sensitization. However, targeting glutamine bioavailability by L-asparaginase (L-ASP) led to a significant reduction in clonogenicity when combined with irradiation. L-ASP reduced extracellular asparagine and glutamine, but the sensitization effects were driven through its depletion of glutamine. L-ASP led to G2/M cell cycle checkpoint blockade. As evidence, there was a respective delay in DNA repair associated with RAD51 downregulation and upregulation of CHOP, contributing to radiation-induced cell death. A radio-resistant PCa cell line was developed, was found to bypass radiation-induced mitotic catastrophe, and was sensitive to L-ASP/radiation combination treatment. Previously, PCa-associated fibroblasts were reported as a glutamine source supporting tumor progression. As such, glutamine-free media were not effective in promoting radiation-induced PCa cell death when co-cultured with associated primary fibroblasts. However, the administration L-ASP catalyzed glutamine depletion with irradiated co-cultures and catalyzed tumor volume reduction in a mouse model. The clinical history of L-ASP for leukemia patients supports the viability for its repurposing as a radio-sensitizer for PCa patients.

A novel glutamine metabolism-related gene signature for prognostic prediction in patients with lung adenocarcinoma

“…L-asparaginase (L-ASP) reduced extracellular asparagine and glutamine, but the sensitization effects were driven through glutamine depletion. L-ASP resulted in G2/M checkpoint blockade [40]. In addition, blocking anaplerotic entry of glutamine into the TCA cycle enhanced the sensitivity of K-Ras mutant cancer cells to cytotoxic drugs [41].…”

Lipid metabolism, amino acid metabolism, and prostate cancer: a crucial metabolic journey

“…Recent research has found that PCa cells show increased Gln metabolism, indicating that Gln metabolism plays a significant driving role in the initiation and progression of PCa. 81 In PCa cells, the synthesis pathway of Gln is activated, and the level of Gln transporter protein is also increased. Studies have shown that the abnormal expression of the transcription factor c-Myc is associated with the activation of the Gln synthesis pathway in PCa cells.…”

A Five Glutamine-Associated Signature Predicts Prognosis of Prostate Cancer and Links Glutamine Metabolism with Tumor Microenvironment

“…Recent studies reveal that many types of tumor growth are highly dependent on glutamine, including non-small cell lung cancer, breast cancer and glioblastoma [ 4 ]. Likewise, glutamine is also one of the key nutrients that drive PCa progression; patients with higher glutamine levels often have poorer prognoses [ 5 ]. A recent study reported that the survival of radiation resistant PCa cells and stem cells relies on a large amount of glutamine, and that the cells undergo growth inhibition after glutamine deprivation [ 6 ].…”