Abstract
BackgroundAngiotensin II (ANGII) and its receptor (AGTR1) have been proposed as significant contributors to metastasis in multiple cancers. Further, high AGTR1 levels are associated with poor epithelial ovarian cancer (EOC) outcomes. However, the mechanistic basis for these effects is unknown. Recent studies have suggested that ovarian cancer metastasis is highly dependent on the formation of multicellular spheroids (MCS). To understand the associations between the ANGII/AGTR1 pathway and cancer outcomes, we evaluated the effects of ANGII on MCS formation by ovarian cancer cells and used a proteomic approach to analyze the mechanistic basis.MethodsWe used the data from the GENT database and immunohistochemistry staining to assess the AGTR1 expression in epithelial ovarian cancer (EOC) patients and to assess its role in cancer progression. Colony formation assay, 3D culture assay, and transwell assays were used to analyze the effect of ANGII on the MCS formation and cell migration. The signaling pathways of AGTR1 and transactivation of epidermal growth factor receptor (EGFR) transactivation were investigated by the western blotting analysis. Xenograft models were used to determine the role of AGTR1 in ovarian cancer metastasis. ANGII release from ovarian cancer cells and ANGII levels in the EOC ascites fluid were measured by immunoassay. A shotgun proteomic approach was used to explore the detail molecular mechanism. Modulation of lipid desaturation and endoplasmic reticulum stress were verified by the in vitro and in vivo functional assays.ResultsAGTR1 expression was negatively correlated with EOC prognosis. AGTR1activation significantly enhanced the MCS formation and cell migration. ANGII triggered both of the classical AGTR1 pathway and the EGFR transactivation. ANGII administration increased peritoneal metastasis. In addition, ovarian cancer cells secreted ANGII and enhanced cancer metastasis in a positive feedback manner. Based on the proteomic data, lipid desaturation was activated by induction of stearoyl-CoA desaturase-1 (SCD1), which suggests that inhibition of SCD1 may significantly reduce MCS formation by increasing endoplasmic reticulum stress.ConclusionsANGII promotes MCS formation and peritoneal metastasis of EOC cells. AGTR1 activation increases the lipid desaturation via SCD1 upregulation, which ultimately reduces endoplasmic reticulum stress in MCS. This mechanism explained the association between high levels of AGTR1 and poor clinical outcomes in EOC patients.
Highlights
Angiotensin II (ANGII) and its receptor (AGTR1) have been proposed as significant contributors to metastasis in multiple cancers
Of the highly upregulated genes, we focused on Stearoyl-CoA Desaturase (SCD1), which is involved in the actions of ANGII in terms of spheroid formation, endoplasmic reticulum (ER) stress, as well as tumorigenicity and metastasis in the xenograft model
High expression of Angiotensin II type 1 receptor (AGTR1) is negatively correlated with prognosis in ovarian cancer patients To validate the AGTR1 expression profile in ovarian cancer patients and to assess its role in ovarian cancer progression, AGTR1 expression was assessed in 902 tumor tissues of ovarian cancer patients and 50 normal ovary tissues from the GENT database
Summary
Angiotensin II (ANGII) and its receptor (AGTR1) have been proposed as significant contributors to metastasis in multiple cancers. To understand the associations between the ANGII/AGTR1 pathway and cancer outcomes, we evaluated the effects of ANGII on MCS formation by ovarian cancer cells and used a proteomic approach to analyze the mechanistic basis. Ovarian cancer is the second most common and the most lethal gynecologic cancer [1]. This lethality is due to late diagnosis of the disease, with > 70% of patients diagnosed with an advanced/metastatic stage (stage III and IV). Ovarian cancer rarely metastasizes via the blood, but rather disseminates throughout the peritoneal cavity. Dissemination is highly aggressive, in a feed-forward manner, posing a unique treatment challenge for advanced/metastatic ovarian cancer. Cancer cells detach from the primary ovarian tumor and spread throughout the peritoneum, affecting multiple organs
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