Mechanism of extracellular citrate uptake and metabolism in cancer; specificity and potential use of gluconate in cancer therapy
Final Report Abstract
We were able to successfully complete work on five out of six work packages. One work package (Aim 2) proved to not be possible, but led nevertheless to new insights into the intriguing regulation mechanism of citrate transporter expression. During the project we designed experiments on the gluconate inhibition, which allowed us to overcome the problems experienced in Aim 2. Based on the results of all 6 work packages, we can summarize our findings as follows: 1. Citrate is an important metabolite in tumour progression, which we found is synthesized and released by cancer-associated stroma. 2. Import of extracellular citrate significantly increases flexibility of cancer metabolism and the increased amount of citrate enables cancer cells to efficiently use different biochemical pathways. 3. Gluconate exhibits a high specificity for pmCiC expressed in cancer cells and did not produce any effects on the benign cells including those expressing pmCiC, but with the function of citrate release. 4. pmCiC is expressed in most cancer cells and cancer-associated stroma of all the human tumour types studied until now. It is not present at significant levels in the benign cells we have tested.
Publications
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(2018) Extracellular Citrate and Cancer Metabolism- Response. Cancer Res. 2018 Sep 1;78(17):5177
Mycielska ME, Geissler EK
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Extracellular Citrate Affects Critical Elements of Cancer Cell Metabolism and Supports Cancer Development In Vivo. Cancer Res. 2018 May 15;78(10):2513-2523
Mycielska ME, Dettmer K, Rümmele P, Schmidt K, Prehn C, Milenkovic VM, Jagla W, Madej GM, Lantow M, Schladt M, Cecil A, Koehl GE, Eggenhofer E, Wachsmuth CJ, Ganapathy V, Schlitt HJ, Kunzelmann K, Ziegler C, Wetzel CH, Gaumann A, Lang SA, Adamski J, Oefner PJ, Geissler EK
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(2019) Potential Use of Gluconate in Cancer Therapy. Front Oncol 2019 Jun 19;9:522
Mycielska ME, Mohr MTJ, Schmidt K, Drexler K, Rümmele P, Haferkamp S, Schlitt HJ, Gaumann A, Adamski J, Geissler EK
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(2020) Extracellular Citrate Fuels Cancer Cell Metabolism and Growth. Front. Cell Dev. Biol. 8:602476
Haferkamp S, Drexler K, Federlin M, Schlitt HJ, Berneburg M, Adamski J, Gaumann A, Geissler EK, Ganapathy V, Parkinson EK and Mycielska ME
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(2021) Cancer-associated cells release citrate to support tumour metastatic progression. Life Sci Alliance. Mar 23;4(6):e202000903
Drexler K, Schmidt KM, Jordan K, Federlin M, Milenkovic VM, Liebisch G, Artati A, Schmidl C, Madej G, Tokarz J, Cecil A, Jagla W, Haerteis S, Aung T, Wagner C, Kolodziejczyk M, Heinke S, Stanton EH, Schwertner B, Riegel D, Wetzel CH, Buchalla W, Proescholdt M, Klein CA, Berneburg M, Schlitt HJ, Brabletz T, Ziegler C, Parkinson EK, Gaumann A, Geissler EK, Adamski J, Haferkamp S, Mycielska ME
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(2021) Extracellular citrate and metabolic adaptations of cancer cells. Cancer Metastasis Rev. Dec 21
Parkinson EK, Adamski J, Zahn G, Gaumann A, Flores-Borja F, Ziegler C, Mycielska ME
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(2021) Potential involvement of extracellular citrate in brain tumor progression. Curr Mol Med. 2021 Mar 2
Jordan K, Stanton EH, Milenkovic VM, Federlin M, Drexler K, Buchalla W, Gaumann A, Adamski J, Proescholdt M, Haferkamp S, Geissler EK, Mycielska ME
