‘” Hyper-Warburg“ Phenomenon - A Rare Complication

Background: Malignant cells rewire metabolism to promote growth and survival through fermentation of glucose to lactate known as Warburg phenomenon; this process occurs even in aerobic conditions. To produce enough ATP the cells must increase the rate of glucose uptake. We report a fatal case of severe hypoglycemia and progressive lactic acidosis in a patient with lymphoma thought to be from Hyper-Warburgism. Case: 57-year-old male with no past medical history presented with diarrhea, abdominal cramping, nausea, vomiting of 1-week duration. At presentation he was hemodynamically stable except for mild tachycardia. Biochemical evaluation showed normal renal function, glucose of 115 mg/dl, sodium of 126 mmol/dL, mild leukocytosis and anemia. CT scan of the abdomen and pelvis showed large retroperitoneal mesenteric portacaval and periportal nodes, biopsy of which revealed CD 30 + T- cell lymphoma. He was discharged with outpatient oncology follow up but re-presented within 1 week with weakness. He was noted to be hypoglycemic with a serum glucose of 55 mg/dl, which was corrected with D50. Laboratory work up showed anemia, mild leukocytosis. Lactic acid was elevated at 5 mmol/dl (0.5–2.2). Chest X ray showed increased peri-hilar markings and he was admitted for presumed sepsis secondary to community acquired pneumonia. Throughout the hospitalization he had persistent hypoglycemia with a serum glucose as low as 33 mg/dl but with only mild neurocognitive symptoms. He was started on a continuous glucose infusion up to 20 g/hr with no significant improvement of the hypoglycemia. He was started on stress dose steroids again without much improvement. Lab evaluation to rule out insulin mediated hypoglycemia was limited an IGF level 1.3 mcg/ml (3.4–6.9), insulin level 2.4 uIU/ml (2.5- 25) with a corresponding serum glucose of 119 mg/dl. He had negative urine and blood cultures. Lactate level continued to increase throughout the hospitalization to as high as 11.3 mmol/dl with the continuous glucose infusion. He unfortunately suffered a cardiac arrest and passed away. Discussion: Warburg phenomenon is an adaptive form of metabolism where malignant cells utilize glucose via the glycolytic pathway irrespective of the oxygen content. This process requires increased glucose uptake to sustain energy production and, in some cases, can result in clinically asymptomatic hypoglycemia and concurrent lactic acidosis. Infusions of dextrose are thought to ‘feed’ the cycle. This severe complication is very rare and associated more commonly with lymphoproliferative disorders as demonstrated in this case. Hypoglycemia and lactic acidosis has been shown to improve only after institution of chemotherapy for treatment of the underlying malignancy. It is important to maintain a high index of suspicion as this cause of hypoglycemia has important therapeutic implications.

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development

Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.

Bioenergetic Profiling of the Differentiating Human MDS Myeloid Lineage with Low and High Bone Marrow Blast Counts

Myelodysplastic syndromes (MDS) encompass a very heterogeneous group of clonal hematopoietic stem cell differentiation disorders with malignant potential and an elusive pathobiology. Given the central role of metabolism in effective differentiation, we performed an untargeted metabolomic analysis of differentiating myeloid lineage cells from MDS bone marrow aspirates that exhibited <5% (G1) or ≥5% (G2) blasts, in order to delineate its role in MDS severity and malignant potential. Bone marrow aspirates were collected from 14 previously untreated MDS patients (G1, n = 10 and G2, n = 4) and age matched controls (n = 5). Following myeloid lineage cell isolation, untargeted mass spectrometry-based metabolomics analysis was performed. Data were processed and analyzed using Metabokit. Enrichment analysis was performed using Metaboanalyst v4 employing pathway-associated metabolite sets. We established a bioenergetic profile coordinated by the Warburg phenomenon in both groups, but with a massively different outcome that mainly depended upon its group mitochondrial function and redox state. G1 cells are overwhelmed by glycolytic intermediate accumulation due to failing mitochondria, while the functional electron transport chain and improved redox in G2 compensate for Warburg disruption. Both metabolomes reveal the production and abundance of epigenetic modifiers. G1 and G2 metabolomes differ and eventually determine the MDS clinical phenotype, as well as the potential for malignant transformation.

MCT4 is a high affinity transporter capable of exporting lactate in high-lactate environments

MCT4 is an H+-coupled transporter expressed in metastatic cancer cells, macrophages, and other highly glycolytic cells, where it extrudes excess lactate generated by the Warburg phenomenon or by hypoxia. Intriguingly, its reported Kmfor lactate, obtained with pH-sensitive probes, is more than an order of magnitude higher than physiological lactate. Here we examined MCT4-rich MDA-MB-231 cells using the FRET sensor Laconic and found a median Kmfor lactate uptake of only 1.7 mM, while parallel estimation in the same cells with a pH probe gave a Kmof 27 mM. The median Kmof MCT4 for lactate was 0.7 mM in MCT4-expressing HEK293 cells and 1.2 mM in human macrophages, suggesting that high substrate affinity is a robust property of the transporter. Probed with the FRET sensor Pyronic, MCT4 showed a Kmfor pyruvate of only 4.2 mM in MDA-MB-231 cells, as opposed to > 150 mM reported previously. We conclude that prior estimates of MCT4 affinity based on pH probes were severely biased by the confounding action of pH regulatory mechanisms. Numerical simulation showed that MCT4, but not MCT1 or MCT2, endows cells with the capability of lactate extrusion in high lactate environments. The revised kinetic properties and novel transport assays may help in developing small-molecule MCT4 blockers for research and therapy.