Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.

Autor: Recouvreux MV; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Grenier SF; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Zhang Y; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Esparza E; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.; Division of Surgical Sciences, Department of Surgery, University of California San Diego, La Jolla, CA, USA., Lambies G; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Galapate CM; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Maganti S; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Duong-Polk K; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Bhullar D; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Naeem R; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Scott DA; Cancer Metabolism Core Resource, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA., Lowy AM; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.; Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA., Tiriac H; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.; Division of Surgical Sciences, Department of Surgery, University of California San Diego, La Jolla, CA, USA., Commisso C; Cancer Metabolism and Microenvironment Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. ccommisso@sbpdiscovery.org.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2024 Jan; Vol. 5 (1), pp. 100-113. Date of Electronic Publication: 2023 Oct 09.
DOI: 10.1038/s43018-023-00649-1
Abstrakt: In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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