Renin angiotensin system (RAS) blocking drugs (angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)) are mainstay treatments for hypertension, heart disease and heart failure. They act to inhibit the systemic RAS, by reducing angiotensin (Ang) II formation or by blocking the Ang II type 1 receptor (AT1R). At the tissue level, the Ang II/AT1R interaction is involved in angiogenesis and proliferation. Several lines of evidence suggest that ACEIs and ARBs could also be effective therapies for the treatment of various types of cancer, including endometrial cancer.
We have demonstrated that 2 other components of the RAS, that is prorenin and (pro)renin receptor ((P)RR), which are essential in tissue RASs, are highly expressed in endometrial cancers, as well as a number of endometrial cancer cell lines. Prorenin bound to the (pro)renin receptor, plays a central role in tissue angiogenesis and proliferation through activation of prorenin and formation of Ang II, or through (P)RR mediated activation of the Wnt and mitogen activated protein kinases (MAPK) signalling pathways. However, the prorenin/(P)RR pathway is yet to be explored in any type of cancer.
We hypothesised that blocking the prorenin/(P)RR interaction could be effective in inhibiting tumourigenesis. To test the role of (P)RR in endometrial cancer; endometrial cancer cells (ECC-1) were treated with either a peptide designed to block prorenin binding to the (P)RR, or with Losartan (an ARB). This study demonstrated that blocking either the (P)RR or AT1R inhibit the expression of the key angiogenic factor (VEGF) in ECC-1 cells.
This study is the first to demonstrate that drugs that block the (pro)renin receptor may be effective anti-cancer agents. We hypothesise that these drugs will be more effective anti-cancer agents than ACEIs or ARBs as they will inhibit both Ang II formation, as well as the Wnt and MAPK signalling pathways.