Ellagic acid induces esophageal squamous cell carcinoma cell apoptosis by modulating SHP‐1/STAT3 signaling

Abstract

Ellagic acid (EA) has been reported to have antiproliferative and antioxidant properties, but its function in esophageal squamous cell carcinoma (ESCC) has not been investigated yet. In the current study, EA was found have a significant anti‐tumor activity in ESCC. In specific, EA inhibited ESCC cell survival in both of a concentration‐ and time‐dependent manner. And our results showed that EA promoted ESCC cell apoptosis, including inducing the cleavages of PARP, and inhibiting the expression of anti‐apoptotic proteins. In mechanistic, EA markedly suppressed STAT3‐driven luciferase activity, and inhibited both of the endogenous and cytokines‐induced STAT3 activation in ESCC cells. Further investigations indicated that EA could significantly upregulate SHP‐1 expression, a negative modulator of STAT3 signaling. In contrast, knockdown of SHP‐1 could attenuate the effects of EA on inhibiting ESCC cell survival. Moreover, we found that EA could inhibit RNF6 expression, an E3 of SHP‐1, and overexpressing RNF6 could also significantly attenuate the effects of EA on inhibiting ESCC cell survival, which further revealed that EA could inhibit STAT3 signaling by modulating RNF6/SHP‐1 axis. Our present study indicated that EA could be as a novel STAT3 inhibitor for the treatment of ESCC.

The bioactivity and applications of pomegranate peel extract: A review

“…During the treatment of breast cancer, EA down-regulates the expression of cyclin-dependent kinase 6 (CDK6) in breast cancer cell lines (Mişe et al, 2014). (Xu et al, 2020). The mechanism of action is…”

RNF6 as an Oncogene and Potential Therapeutic Target—A Review

“…They also demonstrated the influence of the RNF6 on the SHP1/STAT3 pathway. RNF6 activated the STAT3 pathway by modulating ubiquitination and degrading SHP1 in the 26S proteasome [ 11 ]. Similar studies were managed by Liang et al in colorectal cancer.…”

“…They demonstrate that ellagic acid leads to apoptosis of cancer cells and downregulates anti-apoptotic proteins Bcl-2 and Mcl-1. Ellagic acid inhibits the expression of RNF6 , which increases the expression of SHP1 and then inhibits the STAT3 pathway [ 11 ].…”

“…Thanks to its function and involvement in many cancers' pathogenesis, the RNF6 may be a molecular target in cancer therapy. Research is currently conducted with various RNF6 expression inhibitors or compounds that inhibit the activation of RNF6 protein-dependent signaling pathways [10][11][12][13]. There is a large group of proteins with a RING finger domain, but RNF6 has not been fully described [14].…”

Role of Pomegranate in the Management of Cancer

“…The seed coat of the fruit also presents with numerous organic acids including citric acid and ascorbic acid [7]. Among the major biomedical advantages of pomegranate is the anti-cancer activity since pomegranate and its various components has been prove to assist the treatment of cancer and show immunomodulatory activity [8]. This chapter will be discussing on the anti-cancer activity of pomegranate and its antioxidant activity.…”