A novel role for OATP2A1/SLCO2A1 in a murine model of colon cancer

Abstract

Prostaglandin E2 (PGE2) is associated with proliferation and angiogenesis in colorectal tumours. The role of prostaglandin transporter OATP2A1/SLCO2A1 in colon cancer tumorogenesis is unknown. We evaluated mice of various Slco2a1 genotypes in a murine model of colon cancer, the adenomatous polyposis (APC) mutant (Apc ∆716/+) model. Median lifespan was significantly extended from 19 weeks in Slco2a1 +/+/Apc Δ716/+ mice to 25 weeks in Slco2a1 −/−/Apc Δ716/+ mice. Survival was directly related to a reduction in the number of large polyps in the Slco2a1 −/− /Apc ∆716/+ compared to the Slco2a1 +/+/Apc Δ716/+ or Slco2a1 +/−/Apc Δ716/+mice. The large polyps from the Slco2a1 −/− /Apc ∆716/+ mice had significant reductions in microvascular density, consistent with the high expression of Slco2a1 in the tumour-associated vascular endothelial cells. Chemical suppression of OATP2A1 function significantly reduced tube formation and wound-healing activity of PGE2 in human vascular endothelial cells (HUVECs) although the amount of extracellular PGE2 was not affected by an OATP2A1 inhibitor. Further an in vivo model of angiogenesis, showed a significant reduction of haemoglobin content (54.2%) in sponges implanted into Slco2a1 −/−, compared to wildtype mice. These studies indicate that OATP2A1 is likely to promote tumorogenesis by PGE2 uptake into the endothelial cells, suggesting that blockade of OATP2A1 is an additional pharmacologic strategy to improve colon cancer outcomes.

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

“…We found that SLCO2A1 is essential for the PTGS reaction. Blocking SLCO2A1 has been shown to reduce colon cancer tumorigenesis 53 . Importantly, SLCO2A1 can be potently and selectively inhibited by the FDA approved drug suramin 54 .…”

Prostaglandin E2 Pathway Is Dysregulated in Gastric Adenocarcinoma in a Caucasian Population

“…The authors presume that this homeostasis is impaired in gastric tumors due to the negative regulation of SLCO2A1 and, consequently, the negative regulation of PGE 2 degradation, resulting in the enhancement of PGE 2 signaling and gastric tumorigenesis [ 53 ]. Contrary to those reports, a study by Nakanishi et al [ 54 ] suggests an association between higher SLCO2A1 expression in colorectal cancer and poor prognosis. The authors indicate a likely promotion of tumorigenesis by PGE 2 uptake into the endothelial cells via this transporter [ 54 ].…”

Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene

“…In fact, intestinal epithelial-specific Slco2a1-deficient mice has lower susceptibility to experimental colitis as with the model in the study by Zhang et al Although suppressed PGE 2 metabolism in macrophages might contribute to the enhanced PGE 2 concentration, Slco2a1 ΔMP only partially reproduced the systemic knockout phenotype in the present study. As SLCO2A1 is mainly expressed on vascular endothelial cells in the intestinal tracts of mice 47 and humans 12 , a decrease in the clearance of PGE 2 from vascular endothelial cells might also contribute to the increase in the PGE 2 concentration around macrophages in the intestine. Further studies will clarify the role of SLCO2A1 on endothelial cells in intestinal homeostasis.…”