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Cited by 74Connexins and lens biologyCancer, Hypoxia, and MetabolismMetabolism, Diabetes, and Cancer

Connexin-43 channels are a pathway for discharging lactate from glycolytic pancreatic ductal adenocarcinoma cells

Open access
Dovmark, T H, Saccomano, M, Hulikova, A, Alves, F, Swietach, P·2017·Oncogene
DOI 10.1038/onc.2017.71PMC PMC5507299
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Abstract

Glycolytic cancer cells produce large quantities of lactate that must be removed to sustain metabolism in the absence of oxidative phosphorylation. The only venting mechanism described to do this at an adequate rate is H + -coupled lactate efflux on monocarboxylate transporters (MCTs). Outward MCT activity is, however, thermodynamically inhibited by extracellular acidity, a hallmark of solid tumours. This inhibition would feedback unfavourably on metabolism and growth, raising the possibility that other venting mechanisms become important in under-perfused tumours. We investigated connexin-assembled gap junctions as an alternative route for discharging lactate from pancreatic ductal adenocarcinoma (PDAC) cells. Diffusive coupling (calcein transmission) in vitro was strong between Colo357 cells, weaker yet hypoxia-inducible between BxPC3 cells, and very low between MiaPaCa2 cells. Coupling correlated with levels of connexin-43 (Cx43), a protein previously linked to late-stage disease. Evoked lactate dynamics, imaged in Colo357 spheroids using cytoplasmic pH as a read-out, indicated that lactate anions permeate gap junctions faster than highly-buffered H + ions. At steady-state, junctional transmission of lactate (a chemical base) from the spheroid core had an alkalinizing effect on the rim, producing therein a milieu conducive for growth. Metabolite assays demonstrated that Cx43 knockdown increased cytoplasmic lactate retention in Colo357 spheroids (diameter ~150 μm). MiaPaCa2 cells, which are Cx43 negative in monolayer culture, showed markedly increased Cx43 immunoreactivity at areas of invasion in orthotopic xenograft mouse models. These tissue areas were associated with chronic extracellular acidosis (as indicated by the marker LAMP2 near/at the plasmalemma), which can explain the advantage of junctional transmission over MCT in vivo . We propose that Cx43 channels are important conduits for dissipating lactate anions from glycolytic PDAC cells. Furthermore, lactate entry into the better-perfused recipient cells has a favourable alkalinizing effect and supplies substrate for oxidative phosphorylation. Cx43 is thus a novel target for influencing metabolite handling in junctionally-coupled tumours.

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  • Cx43 levels are low in MIA PaCa-2 primary tumors but increase in areas of invasion and metastasis.

    “we showed that Cx43 levels are low in MIA PaCa-2 primary tumors but increase in areas of invasion and metastasis”

    From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [48]

    The Results section reports no Cx43 immunoreactivity in the MIA PaCa-2 primary tumor and markedly increased staining in invading cells. It also says Cx43 staining was weak or absent in most lung metastases, although some metastatic lesions were positive; the claim overgeneralizes the metastatic finding. (LLM, conf=0.88)

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  1. Moll W, Gros G. Combined glycolytic production of lactate(−) and ATP(4−) derived protons (=dissociated lactic acid) is the only cause of metabolic acidosis of exercise—a note on the OH(−) absorbing function of lactate (1−) production. J Appl Physiol 2008; 105: 365. 18680794

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Authors
Dovmark, T. H., Saccomano, M., Hulikova, A., Alves, F., & Swietach, P.
Affiliations
  • University of Oxford (GB)
  • Max Planck Institute of Experimental Medicine (DE)
  • Universitätsmedizin Göttingen (DE)
Corresponding author
Swietach, P
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2017-04-03
Volume
36
Issue
32
Pages
4538-4550
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2017.71
PMC
PMC5507299
OpenAlex
W2604827133
Cited by
74
References
45
Citations by year
2026: 6 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 11 · 2020: 9 · 2019: 14 · 2018: 4 · 2017: 2
FWCI
3.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • Max Planck Digital Library (submittedVersion, other-oa)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders
  • European Commission (289648, FP7-PEOPLE-2011-ITN, FP7-PEOPLE-2011)
  • FP7 People: Marie-Curie Actions (FP7-PEOPLE-2011-ITN, 289648)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
connexin 43, gap junctions, lactate efflux, pancreatic ductal adenocarcinoma, glycolysis, extracellular acidosis, lactate transport, monocarboxylate transporters, tumor spheroids, cytoplasmic pH, tumor invasion, oxidative phosphorylation
MeSH terms
Acidosis, Lactic, Animals, Glycolysis, Humans, Male, Mice, Nude, Neoplasm Transplantation, Pancreatic Neoplasms, Phosphorylation, Gap Junctions, Connexin 43, Spheroids, Cellular, Lactic Acid, Carcinoma, Pancreatic Ductal, Monocarboxylic Acid Transporters, RNA, Small Interfering, Cell Line, Tumor, Mice, Lysosomal-Associated Membrane Protein 2

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