Mitochondrial uncoupling & metabolic network disruption in hepatocellular carcinoma

Oncotarget recently published "Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma" which reported that the authors studied the anti-HCC effect of FH535 and a novel derivative Y3, on proliferation, mitochondrial function, and cellular metabolism focusing on the three key substrates, glutamine, glucose, and fatty acids.

FH535 and Y3 disrupted mitochondrial redox control in HCC cells that resulted from uncoupling mechanisms that increased proton leakage and decreased ATP production leading to apoptosis.

The uncoupling effects of the sulfonamides in HCC cells were supported by the loss of activity of the methylated analogs.

These sulfonamides, FH535 and Y3, targeted glutamine and fatty acid metabolism and caused HCC cell reprogramming towards the preferential use of glucose and the glycolytic pathway.

FH535, and Y3, demonstrated potent anti-HCC activity by targeting OXPHOS, increasing dangerous levels of ROS, and reducing ATP production.

Dr. Roberto Gedaly from The University of Kentucky said, "Hepatocellular carcinoma (HCC) is the most common primary liver cancer with more than 800,000 new cases annually."

The Wnt/β-catenin pathway is critical for HCC cell proliferation, progression, and stemness, and this pathway is aberrant in 30–50% of the HCC tumors.

Figure 10: Relative expression of SLC1A5 and SLC7A5 mRNA were determined by real time-PCR after 48 treatment of Huh7 cells with 10 μM of the indicated compounds using B2M gene for normalization. Values are represented as mean ± SD, ^*p < 0.05 vs. control.

In recent years, the authors reported that 2,5-dichloro-N- benzenesulfonamide, a sulfonamide that targets this pathway and alters mitochondrial respiration and the autophagic process, is acting alone and in combination with other drugs against HCC in vitro and in vivo.

They recently reported that FH535 affected the Wnt/β-catenin pathway functioning as a mitochondrial “proton uncoupler” in colon cancer cells.

Another group studied how sorafenib, a drug commonly used in the treatment of advanced HCC, acts as a mitochondrial uncoupler at low doses.

The Oncotarget authors now report a study of the functional link between the uncoupler activities of FH535 and a new analog of FH535, 2,5-dichloro-N- benzenesulfonamide and the methylated analogs and Y3 on HCC activity.

The Oncotarget authors now report a study of the functional link between the uncoupler activities of FH535 and a new analog of FH535, 2,5-dichloro-N- benzenesulfonamide and the methylated analogs and Y3 on HCC activity.

The Gedaly Research Team concluded in their Oncotarget Research Paper that the FH535 and Y3 disruption of mitochondrial redox control in HCC cells resulted from uncoupling mechanisms that increased proton leakage and decreased ATP production leading to apoptotic cell death.

The uncoupling effects of the sulfonamides in HCC cells were supported by the loss of activity of the methylated analogs.

The accumulation of ROS significantly contributed to cell damage after the impaired autophagic machinery.

Lastly, the sulfonamides FH535 and Y3 also targeted glutamine and fatty acid metabolism and caused HCC cells to reprogram their metabolic activity towards the preferential use of glucose and the glycolytic pathway.

A detailed understanding of the metabolic alterations induced by small molecules and combination therapies will provide future therapies to treat this difficult neoplasm.

DOI - https://doi.org/10.18632/oncotarget.27680

Full text - https://www.oncotarget.com/article/27680/text/

Correspondence to - Roberto Gedaly - rgeda2@uky.edu

Keywords - hepatocellular carcinoma, proton uncouplers, Wnt/β-catenin pathway, glutamine metabolism, mitochondria

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