AGTR1 potentiates the chemotherapeutic efficacy of Cisplatin in esophageal carcinoma through elevation of intracellular Ca 2+ and induction of apoptosis

Abstract

Abstract Cisplatin is one of the principal chemotherapeutic agents used for esophageal cancer (EC) treatments, and EC mortality is still high. It is imperative to find new therapeutic targets and approaches to potentiate the chemotherapeutic efficacy of Cisplatin. Previous studies proposed that Angiotensin II receptor type 1 (AGTR1) is a therapeutic target in multiple cancer types. Here, we performed RNA-sequencing analysis of EC tissues and normal esophageal tissues, and identified AGTR1 as a differentially expressed gene that is markedly downregulated in recurrent and metastasized EC. AGTR1 expression in esophageal squamous cell carcinoma cell lines KYSE-150 and EC109 promoted their chemosensitivity to cisplatin both in vitro and in vivo. Additionally, AGTR1 expression suppressed the metastasis-relevant traits of EC cells, as evidenced by reduced cell migration, invasion, and wound healing in EC cells with higher AGTR1 expression levels. Moreover, AGTR1 expression in EC cells upregulated intracellular Ca2+ levels, increased the losses of ATP levels and mitochondrial membrane potentials, which was accompanied with enhanced mitochondrial pathway apoptosis. Notably, either AGTR1 overexpression or treatments with the calcium channel blocker fendiline caused Ca2+ influx and promoted the mitochondria-dependent apoptosis in KYSE-150 cells in vitro. These effects were augmented when both AGTR1 overexpression and fendiline stimulation were imposed in the absence or presence of Cisplatin treatments. Furthermore, fendiline administration enhanced the chemosensitivity of Cisplatin in an EC xenograft mouse model. Collectively, our findings offer an alternative treatment option and provide mechanistic insight into using fendiline to potentiate the chemotherapy efficacy of Cisplatin in EC treatments.