Oncometabolite lactate promotes tumor growth

A high rate of glycolysis uncoupled from oxidative phosphorylation (OXPHOS) supports cancer cell growth under hypoxia and proliferation independently of oxygen bioavailability. In established tumors, oxygenated cancers cells are also fueled with various substrates in order to optimally produce ATP with OXPHOS. These metabolic activities are paced at high rate to fulfill the aggressive tumor agenda. They are associated with the production and release of protons from various sources, including decarboxylation reactions in the TCA cycle and in the oxidative arm of the pentose phosphate pathway, deamination reactions in amino acid metabolism, and ATP hydrolysis. pH in the cytosol of glycolytic cancer cells is maintained at slightly alkaline values promoting glycolysis thanks to the activity of various proton pumps and transporters. While membrane-bound V-ATPase is an active pump requiring ATP, passive transport systems include the sodium-proton exchanger NHE-1, carbonic anhydrases (CAs) IX and XII that function in tandem with sodium-bicarbonate cotransporters (NBCs), and lactate-proton symporters of the monocarboxylate transporter (MCT) family. All except MCTs ultimately depend on ATP, which is consumed by NaK-ATPase for sodium homeostasis in the cytosol. MCTs differ from other pH regulatory systems by their ability to transport lactate, which we recently identified to be an oncometabolite. Lactate is indeed at the core of a metabolic symbiosis between glycolytic cancer cells (that consume glucose and produce lactate) and oxidative cancer cells (that consume lactate oxidatively preferentially to glucose). Lactate also promotes autophagy for the survival of oxygenated cancer cells subject to oxidative stress. As a hypoxia-mimetic, lactate further triggers angiogenesis by activating transcription factor HIF-1 in cancer cells and HIF-1 and NF-κB in the vascular endothelium. Based on these many activities of lactate, inhibitors of lactate uptake targeting MCT1 expressed at the plasma membrane of oxidative cancer cells have been identified. They are currently being validated for therapy. Supported by ERC Starting Grant 243188 TUMETABO, IAP grant #UP7-03 from Belspo, the Communauté Française de Belgique (ARC 14/19-058), the Belgian F.R.S.-FNRS, and the Belgian Foundation against Cancer

ICTR Quarterly Bibliography : Bibliographie Trimestrielle du TPIR.

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Judgement and sentence of the prosecutor V. Ferdinand Nahimana; Jean-Bosco Barayagwiza; Hassan Ngeze; case No.ICTR-99-52-T

Document collected by the University of Texas Libraries from the web-site of the Reseau Documentaire International Sur La Region Des Grands Lacs Africains (International Documentation Network on the Great African Lakes Region). The Reseau distributes "gray literature", non-published or limited distribution government or NGO documents regarding the Great Lakes area of central Africa including Rwanda, Burundi, and the Democratic Republic of Congo.UT Librarie