Angiotensin II promotes ovarian cancer spheroid formation and metastasis by upregulation of lipid desaturation and suppression of endoplasmic reticulum stress

Abstract

Background Angiotensin 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. Methods We 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. Results AGTR1 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. Conclusions ANGII 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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1127-x) contains supplementary material, which is available to authorized users.

Targeting AGTR1/NF-κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma

“…Furthermore, AGTR1 overexpression has also been linked to multiple human malignancies including ovarian, renal, pancreatic, breast, and brain [8] , [9] , [10] , [11] . While in breast cancer (BCa), significant overexpression of AGTR1 represents a subpopulation of Human epidermal growth factor (HER2)-negative and estrogen receptor (ER) positive patients [12] , in ovarian cancer its high expression has been linked to metastasis by promoting multicellular spheroid formation [13] . Mechanistically, overexpression of AGTR1 has been observed to inhibit apoptosis while promoting angiogenesis, cell proliferation and inflammation [14] , [15] .…”

A signature of seven immune-related genes predicts overall survival in male gastric cancer patients

“…In GC, the utility of AGTR1 inhibitor signi cantly suppress GC cell proliferation and stromal brosis [28]. It has been proved that AGTR1 could enhance malignant phenotype of several cancer cells to promote tumor progression [29][30][31].…”

Involvement of ACE2/Ang-(1-7)/MAS1 Axis in the Regulation of Ovarian Function in Mammals

“…Recently Zhang et al [ 99 ] obtained convergent results indicating that high AT1 expression was negatively correlated with survival time for grade 1 and 2 ovarian tumor patients. Ang II was again found to increase OC cell proliferation by AT1 receptor, but the results were significant only in the 3D culture model.…”

“…Secretion of Ang II by ovarian cells was observed in in vitro cell lines, xenograft mouse models, and patient samples. Zhang et al [ 99 ] suggest that AGTR1 activates ERK and AKT signaling, as well as transactivation of the EGFR pathway. Furthermore, Gene Ontology (GO) analysis showed that Ang II upregulated multiple SREBP pathway-related genes and downregulated genes of JNK cascade.…”

“…Furthermore, Gene Ontology (GO) analysis showed that Ang II upregulated multiple SREBP pathway-related genes and downregulated genes of JNK cascade. The authors conclude that Ang II upregulates SCD1, which promotes OC progression and metastasis by improving the lipid desaturation and relieving endoplasmic reticulum stress during the formation and growth of MCS [ 99 ].…”