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Lookup NU author(s): John Moir, Anna Long, Dr Beate Haugk, Jeremy French, Richard Charnley, Professor Derek Manas, Professor Steve Wedge, Professor Jelena Mann, Stuart Robinson, Steven White
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OBJECTIVES: Pancreatic stellate cells (PSCs) play a key metabolic role within the tumor microenvironment (stroma) of pancreatic ductal adenocarcinoma (PDAC), being glycolytic and associated with protumorigenic acidification from excess lactate. This study investigates the clinical significance of glycolytic enzyme lactate dehydrogenase (LDH) and determines efficacy of the novel pan-LDH inhibitor Galloflavin. METHODS: An in vitro Transwell system was adopted for coculture of PSCs and 3 PDAC cell lines (MIA PaCa-2, PANC-1, and BxPC-3). Cells were treated with Galloflavin, and outcomes were analyzed regarding proliferation, apoptosis, lactate production, and glycolytic enzyme protein expression. Immunohistochemical staining for lactate dehydrogenase B (LDHB) was performed on 59 resected PDAC tumors annotated for clinical outcome. RESULTS: Galloflavin reduced PDAC proliferation in monoculture (P < 0.01); however, in co-culture with PSCs, an antiproliferative effect was only evident in PANC-1 (P = 0.001). An apoptotic effect was observed in MIA PaCa-2 and BxPC-3 in coculture (P < 0.05). A reduction in media lactate was observed in coculture (P < 0.01) with PSCs. Immunohistochemistry revealed stromal and tumoral LDHB expression had no impact on survival. CONCLUSIONS: Galloflavin has the potential to neutralize the acidic PDAC microenvironment and thereby reduce tumor invasiveness and metastasis. Patients with lower LDHB expression are more likely to be beneficial responders.
Author(s): Moir JAG, Long A, Haugk B, French JJ, Charnley RM, Manas DM, Wedge SR, Mann J, Robinson SM, White SA
Publication type: Article
Publication status: Published
Journal: Pancreas
Year: 2020
Volume: 49
Issue: 10
Pages: 1364-1371
Print publication date: 01/11/2020
Acceptance date: 02/04/2016
ISSN (print): 0885-3177
ISSN (electronic): 1536-4828
Publisher: Lippincott, Williams & Wilkins
URL: https://doi.org/10.1097/MPA.0000000000001689
DOI: 10.1097/MPA.0000000000001689
PubMed id: 33122526
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