Cystathionine gamma-lyase (CTH) contributes to clear cell ovarian cancer progression by increasing HIF1α expression and has been identified as a potential therapeutic target in preclinical models.
Researchers at the BC Cancer Research Institute, Vancouver, investigated the role of CTH—a transsulfuration pathway enzyme highly expressed in clear cell ovarian cancer (CCOC). Using CRISPR/Cas9 gene editing, they knocked out CTH in four human CCOC cell lines. The modified cells showed reduced viability and impaired motility, alongside decreased invasive behavior. They also accumulated higher levels of reactive oxygen species and had lower glutathione-to-glutathione disulfide ratios, indicating disrupted redox balance. Lipid peroxidation markers were also elevated. The findings were published in The Journal of Pathology.
In mouse models, tumors derived from CTH-deficient OVISE cells averaged 2 mm in size, compared with 8 mm tumors in controls. Moreover, none of the mice implanted with CTH knockout cells developed lung metastases. A second model using tail-vein injection of RMG-I cells confirmed that CTH loss greatly limited lung colonization.
Mechanistically, CTH promoted cancer progression by increasing protein levels of hypoxia inducible factor 1-alpha (HIF1α), a transcription factor associated with tumor aggressiveness. This effect was independent of hydrogen sulfide signaling and not due to altered mRNA levels or protein degradation. Restoring HIF1A in CTH-deficient cells recovered their metastatic potential, both in vitro and in vivo. Analysis of 84 human tumor samples supported the association between CTH and HIF1α expression.
Importantly, CTH knockout cells were more sensitive to cisplatin, with a 60 percent drop in viability following treatment.
The findings indicate that CTH contributes to CCOC progression by modulating oxidative stress and hypoxic signaling pathways. The researchers concluded that CTH may be a viable target to reduce metastasis and enhance chemotherapy response in this chemoresistant ovarian cancer subtype.
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