Inhibiting serine/arginine-rich protein kinase-1 (SRPK1) in cholangiocarcinoma (CCA) cells can effectively reduce angiogenesis, according to a new study published in Toxicology in Vitro. This finding suggests that SRPK1 inhibitors could be potential therapeutic targets to treat the disease.

SRPK1 is an enzyme that plays a crucial role in regulating different aspects of mRNA splicing and that is known to be overexpressed in many types of cancers. However, its potential role in CCA has never been studied before.

Here, a team of researchers led by Kanokpan Wongprasert, PhD, from the Department of Anatomy, Faculty of Science, Mahidol University in Bangkok, Thailand examined the expression of SRPK1 in CCA cells and the effects of selectively inhibiting it using SPHINX31.


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They found that even though SPHINX31 did not inhibit the viability and proliferation of CCA cells, it decreased the expression of the proangiogenic VEGF-A165a isoform. Moreover, it attenuated the phosphorylation and nuclear localization of SRSF1, a critical regulator that controls both RNA splicing and stability in the nucleus. Finally, it increased the ratio of VEGF-A165b over total VEGF-A proteins.

When they grew human umbilical vein endothelial cells in a conditioned medium from SPHINX31-treated CCA cells, the researchers found that the migration of the cells slowed down and the formation of tubes decreased.

“Targeting SRPK1 in CCA cells effectively attenuates angiogenesis by suppressing pro-angiogenic VEGF-A isoform splicing,” the researchers wrote.

“We have demonstrated that targeting of SRPK1 presents a promising area of investigation and therapeutic strategy for modulating angiogenesis, as an effective adjuvant with chemotherapeutic drugs for CCA treatment.

CCA is the second most common malignancy of the liver. Curative surgery is currently the only option for long-term survival but only a few patients are considered candidates for the procedure. The 5-year survival rate for patients with unresectable tumors is close to 0%.

Reference

Supradit K, Boonsri B, Duangdara J, et al. Inhibition of serine/arginine-rich protein kinase-1 (SRPK1) prevents cholangiocarcinoma cells induced angiogenesis. Toxicol in Vitro. 2022;11;82:105385. doi:10.1016/j.tiv.2022.105385