A75 TARGETING THE WARBURG EFFECT IN HEPATOCELLULAR CARCINOMA CELLS
Bibliographic record
Abstract
The avid consumption of glucose (Glu) with concomitant lactate production by malignant cells is called the Warburg effect (WE). As most invasive tumours harbour this feature, this has proven of great clinical importance in detecting malignancies with PET scans. Unfortunately, in the liver, the detection of tumors is often compromised by the strong intrinsic Glu metabolic activity. Understanding the manner by which hepatocellular carcinoma (HCC) cells use Glu to proliferate is essential if we want to bypass the aforementionned difficulty. Recently, targeting molecular mechanisms involved in the WE such as lactate dehydrogenase (LDH) has been advocated as a very promising anti-cancer target. We hypothesized that the modulation of LDH which catalyzes the conversion of pyruvate to lactate might have an impact on HCC cell tumorigenicity, since the production of lactate has been shown to increase tumor invasion. We generated a mouse hepatoma cell line Dt81Hepa1-6 (Dt) derived from Hepa1-6 (H1-6) cells that displays greater tumorigenicity in vivo. We hypothesized that this increased tumorigenicity involved the WE. Cells were cultured in 25mM Glu over a period of 24-48h. Glu uptake was assessed using a fluorescent Glu analog, 2-NBDG. mRNA and metabolite quantification were respectively measured by qPCR and HPLC. Aerobic glycolysis was inhibited using increasing doses of sodium oxamate (SODOX), a classic inhibitor of LDH, to reduce lactate production. LDH activity was measured by the Biochemical core facility of CRCHUM. MTT assay was used to test the dose-response effects of SODOX on cell viability. Cell Doubling Time (CDT) was evaluated every 24h for 72h with SODOX (100 mM). Dt showed an increased ability to uptake Glu in low extracellular Glu in comparison with H1-6 (3 ± 0.3 vs 1.4 ± 0.1DO/μg prot, P<0.01). Increasing the extracellular Glu concentration led to an increase in Glu uptake only in Dt cells (P<0.001). qPCR and metabolite analysis showed that Dt displayed a higher glycolytic rate than H1-6, with greater ATP production (P<0.001). We then investigated the effect of SODOX on these cells. First, LDH acticvity was reduced in a dose-response manner after 24h with SODOX (100mM, P<0.01). MTT revealed that SODOX dose-dependently decreased cell viability of both H1-6 and Dt cells but that Dt were significantly more resistant at 100mM SODOX (43 ± 1.5 vs 55 ± 2.6, P<0.01). Finally, CDT revealed that SODOX significantly slowed Dt proliferation; this effect was even more pronounced on H1-6 (P<0.001). These results suggest that the WE is effective in HCC cells and that increased tumorigenesis is associated with metabolic changes in glucose metabolism that favor ATP production. The WE represents a potentially remarkable new target to treat HCC. Our preliminary results suggest that decreasing LDH activity is one of the ways to achieve this goal. CHAIRE NOVARTIS DE LA FONDATION CANADIENNE DU FOIE DE L’UNIVERSITE DE MONTREAL
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".