Endometrial cancer is the most common gynaecological malignancy. Australia has one of the highest rates of endometrial cancer in the world and its incidence is increasing.
Tissue renin angiotensin systems (RASs) are known to stimulate angiogenesis, cell proliferation and migration. These actions potentiate cancer growth and spread. We have previously demonstrated that endometrioid endometrial cancers express both prorenin and prorenin receptor ((P)RR) mRNA and have significantly greater levels of these proteins than normal adjacent endometrial tissue. Prorenin acting via the (P)RR can activate both RAS dependent and independent signalling pathways.
We have studied the effects of the blockade of components of the (P)RR/prorenin angiotensin system in 3 endometrial cancer cell lines, Ishikawa, HEC-1A and AN3CA. Both Ishikawa and HEC-1A endometrial cancer cell lines express (P)RR and renin mRNA, however levels of (P)RR are much higher in Ishikawa cells. Transfection of Ishikawa and HEC-1A cell lines with a ((P)RR) siRNA resulted in 90% knockdown of PRR mRNA and reduced cell viability in Ishikawa but not HEC-1A cells. Renin inhibitors (Aliskiren and VTP-27999) reduced cell viability in both cell lines (Ishikawa, HEC-1A), whereas, in AN3CA cells Aliskiren alone reduced cell viability. The (P)RR inhibitor, HRP, and the angiotensin II type 1 receptor (AT1R) inhibitor, losartan, had no effect on cell viability in any of the 3 cell lines. Another AT1R antagonist, telmisartan, which also acts as a selective modulator of peroxisome proliferator-activated receptor gamma (PPAR-γ), a central regulator of insulin and glucose metabolism did however reduce cell viability in all 3 cell lines (Ishikawa, HEC-1A and AN3CA).
The (P)RR/prorenin angiotensin system, may be may be functionally important for endometrial cancer growth and development, either through activation of Ang II/AT1R pathways or directly, through ((P)RR) signalling. Thus, (P)RR and its downstream signalling pathways may be therapeutic targets for treating endometrial cancer.