Abstract 4136: Effect of prorenin receptor PRR knock down and telmisartan on endometrial cancer growth

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.4136-4136
• Main Authors: Mohammed, Riazuddin, Delforce, Sarah J., Wang, Yu, Verrills, Nicole M., Lumbers, Eugenie R., Pringle, Kirsty G.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-4136

Endometrial cancer is the most common gynaecological malignancy and its incidence is increasing. Tissue renin angiotensin systems (RAS) are known to stimulate angiogenesis, cell proliferation and migration. All of 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. Therefore we hypothesized that endometrial cancer growth can be inhibited by drugs that block Ang II/AT1R interactions and prorenin/(P)RR mediated signaling pathways. To determine the functional role of (P)RR in endometrial cancer growth, we used siRNA transfection to knock down (P)RR expression in three endometrial cancer cell lines (Ishikawa, HEC-1A and AN3CA) at 24h, 48h, 72h & 96h. The effect of RAS blockers on cell viability was also assessed by Resazurin assay at 48h in the three endometrial cancer cell lines. All three of the endometrial cancer cell lines examined (Ishikawa, HEC-1A and AN3CA) expressed (P)RR and prorenin mRNA, however levels of (P)RR were much higher in Ishikawa cells. Transfection of the three cell lines with a (P)RR siRNA resulted in 90% knockdown of (P)RR mRNA expression and reduced the cell viability of both Ishikawa and AN3CA but not HEC-1A cells, as measured by a resazurin assay after 48h incubation. Aliskiren (a renin inhibitor) inhibited Ishikawa cell growth by 20%. There was no effect of Aliskiren on cell viability in HEC-1A and AN3CA cell lines. Perindoprilat (an ACE inhibitor) and Losartan (an angiotensin II type 1 receptor (AT1R) inhibitor) had no effect on cell viability in any cell line. Another AT1R antagonist, telmisartan, which also acts as a selective agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), did however significantly reduce cell viability in all cell lines (Ishikawa 75%, HEC-1A 50% and AN3CA 60%). Removal of the prorenin receptor inhibits the growth and development of some endometrial cancer cell lines. Only telmisartan, which has properties additional to Ang II antagonism, was effective in inhibiting endometrial cancer cell growth. (P)RR knockdown and telmisartan are therefore potential therapeutic drugs for the treatment of endometrial cancer. Citation Format: Riazuddin Mohammed, Sarah J. Delforce, Yu Wang,