Novel Therapeutic Strategies Against Endometrial Cancer

In a new study, researchers investigated the role of the (pro)renin receptor in endometrial cancer cell growth.

In the United States and worldwide, the incidence and mortality rates of endometrial cancer among women have been increasing in recent years. While endometrial cancer is highly treatable, the primary treatment is a surgical hysterectomy. Hysterectomies can have serious side effects and painful personal consequences.

The rise of this gynecological cancer has driven researchers to investigate viable targets and biomarkers for use in endometrial cancer diagnosis, prognosis prediction and alternative therapeutic strategies. In a new study, researchers—from the University of Newcastle, University of Technology Sydney, Monash University, and the University of Melbourne—investigated the (pro)renin receptor ((P)RR) and its role and interactions in the biology of endometrial cancer. Their trending research paper, published in Oncotarget on April 1, 2022, was entitled, “Role of the prorenin receptor in endometrial cancer cell growth.”

The Study

The ATPase H(+)-transporting lysosomal accessory protein 2 (ATP6AP2) gene encodes the (P)RR, and the terms can be used interchangeably. The (P)RR is a membrane protein that plays a key role in activating the renin-angiotensin system (RAS). It is widely expressed in various tissues and organs, such as the kidney, heart, lung, and endometrium. In endometrial cancer, the (P)RR has been shown to be overexpressed in cancerous tissue compared to normal endometrium tissue. Expression levels of this receptor are associated with endometrial cancer progression and poor prognosis. However, the precise role of the (P)RR in endometrial cancer has remained largely unknown.

In this in vitro analysis, the researchers first conducted a proteomic screening of the ATP6AP2 protein and mRNA expression in three endometrial cancer cell lines: Ishikawa, AN3CA and HEC-1-A. To silence (P)RR expression in each of the three cell lines, the team employed an siRNA-mediated knockdown of ATP6AP2. Next, they used an xCELLigence RTCA DP instrument that measures cell invasion and migration to evaluate the impact of (P)RR knockdown on cellular proliferation. They then used a resazurin assay to examine the effects of (P)RR knockdown on cancer cell viability.

A proteomic screening was also carried out to explore potential pathways (P)RR is involved in in the physiology of endometrial cancer. In addition, the enzyme-linked immunosorbent assay (ELISA) was used to measure circulating soluble prorenin receptor (s(P)RR) levels in the endometrial cancer cell lines (before and after the knockdown of (P)RR expression) and in plasma and uterine fluid samples donated by endometrial cancer patients.

The Results

The researchers believe this study was the first to report on the mRNA and protein expression of (P)RR in three endometrial epithelial cancer cell lines. Results showed that the (P)RR was critical for endometrial cancer cell growth—contributing both to its cell viability and proliferative capacity. However, the data confirmed their previous observations that (P)RR mRNA and protein levels do not correlate with tumor grade in primary endometrial tumor samples. The researchers stated that the (P)RR’s contribution to endometrial cancer progression is likely mediated through proteins that were reduced after (P)RR expression knockdown, such as MGA, SLC4A7, SLC7A11, or DHRS2.

“Notably, (P)RR mRNA and protein levels were independent of tumour grade, with the highest expression detected in Ishikawa cells (grade 1), followed by AN3CA cells (grade 3) and finally HEC-1-A cells (grade 2).

They also observed that s(P)RR levels in their plasma samples were significantly higher in patients with endometrial cancer than in age-matched controls. Intriguingly, as cancer grade increased, so did s(P)RR levels. This indicated that s(P)RR may be a viable predictive or diagnostic marker for patients with endometrial cancer.

“Our data confirms that the (P)RR is important for endometrial cancer development, contributing to both its viability and proliferative capacity. Moreover, our quantitative proteomics approach uncovered several putative protein interactions and pathways that rely on (P)RR for disease progression and may represent novel therapeutic targets in the treatment of endometrial cancer. Finally, we contend that circulating s(P)RR levels may have substantial potential as a novel biomarker for cancer diagnosis and prognosis.”

Conclusion

This study sheds new light on the role of the (P)RR in endometrial cancer. The researchers suggest that future studies should aim to vet their findings in endometrial cancer patients.

“Collectively, our data indicate that targeting the (P)RR by an siRNA approach (such as in this study) or with an alternative anti-(P)RR monoclonal antibody approach currently being explored by Wang et al. [29] may be a viable therapeutic strategy against endometrial cancer.”

Click here to read the full research paper published by Oncotarget.

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Oncotarget is an open-access journal that publishes primarily oncology-focused research papers in a continuous publishing format. These papers are available at no cost to readers on Oncotarget.com. Open-access journals have the power to benefit humanity from the inside out by rapidly disseminating information that may be freely shared with researchers, colleagues, family, and friends around the world.

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