Aspartate beta-hydroxylase (ASPH) may be involved in chemoresistance in cholangiocarcinoma, according to a new study presented in a poster at the 2021 annual meeting of the American Association for the Study of Liver Diseases. ASPH is a 2-oxoglutarate (2-OG)-dependent enzyme that is highly expressed in cholangiocarcinoma.
“Increased 2-OG antagonizes chemotherapeutic effect in cholangiocarcinoma progression,” the authors of the poster wrote. They hypothesized that targeting ASPH may increase DNA damage caused by chemotherapy, thereby improving the efficacy of chemotherapy in cholangiocarcinoma.
Previous research suggested that 2-OG-dependent dioxygenases may play a role in DNA damage responses, thereby causing chemoresistance in patients with cholangiocarcinoma.
A team of researchers led by Chiung-Kuei Huang, PhD, from the Department of Pathology and Laboratory Medicine at Tulane University in New Orleans, Louisiana examined the levels of 2-OG in the serum of patients with cholangiocarcinoma to better understand how 2-OG may antagonize the effects of chemotherapy. The patients were grouped into 1 of 3 categories: progressive disease, partial response, or stable disease following chemotherapy.
They found that patients with progressive disease had significantly higher 2-OG levels in their serum than patients with stable disease and partial response.
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Moreover, treating cholangiocarcinoma cells with 2-OG reduced the effect of chemotherapy as well as DNA damage response. The overexpression of ASPH mimicked the effects of 2-OG on DNA damage. This suggested that ASPH may play an important role in chemoresistance, the authors said.
“We found that knockdown of ASPH improves the therapeutic potential of chemotherapy in [cholangiocarcinoma] cells,” they wrote.
When they targeted ASPH with a specific small-molecule inhibitor in vitro, the effect of chemotherapy was enhanced. The expression of ASPH did not change the expression of 2 important regulators of DNA damage response. Finally, 2 preclinical studies in cholangiocarcinoma models have also shown that targeting ASPH could improve the effect of chemotherapy.
Nagaoka K, Ji C, Bai X, et al. Elevated 2-oxoglutarate antagonizes chemotherapeutic effects in cholangiocarcinoma by targeting DNA damage response signaling pathways. Poster presented at: The Liver Meeting 2021: November 12-15, 2021; Virtual.