Resveratrol Mediates the Apoptosis of Triple Negative Breast Cancer Cells by Reducing POLD1 Expression

Abstract

Resveratrol (RSV) is known to possess anticancer properties in many types of cancers like breast cancer, in which POLD1 may serve as a potential target. However, the anticancer mechanism of RSV on triple negative breast cancer (TNBC) remains unclear. In the present study, the antitumor effects and mechanism of RSV on TNBC cells were analyzed by RNA sequencing (RNA-seq), which was then verified via cell counting kit-8 (CCK8), immunofluorescence, immunohistochemistry, Western Blot (WB), flow cytometry, and hematoxylin-eosin (HE) staining. According to the corresponding findings, the survival rate of MDA-MB-231 cells gradually decreased as RSV treatment concentration increased. The RNA-seq analysis results demonstrated that genes affected by RSV treatment were mainly involved in apoptosis and the p53 signaling pathway. Moreover, apoptosis of MDA-MB-231 cells induced by RSV was observed to be mainly mediated by POLD1. When treated with RSV, the expression levels of full length PARP1, PCNA, and BCL-2 were found to be significantly reduced, and the expression level of Cleaved-PARP1 as well as Cleaved-Caspase3 increased significantly. Additionally, the mRNA expression of POLD1 was significantly reduced after treatment with RSV, and the protein expression level was also inhibited by RSV in a concentration-dependent manner. The prediction of domain interaction suggested that RSV may bind to at least five functional domains of the POLD1 protein (6s1m, 6s1n, 6s1o, 6tny and 6tnz). Furthermore, after RSV treatment, the anti-apoptotic index (PCNA, BCL-2) of MDA-MB-231 cells was found to decrease while the apoptosis index (caspase3) increased. Moreover, the overexpression of POLD1 reduced the extent of apoptosis observed in MDA-MB-231 cells following RSV treatment. Moreover, animal experimental results showed that RSV had a significant inhibitory effect on the growth of live tumors, while POLD1 overexpression was shown to antagonize this inhibitory effect. Accordingly, this study’s findings reveal that RSV may promote the apoptosis of TNBC cells by reducing the expression of POLD1 to activate the apoptotic pathway, which may serve as a potential therapy for the treatment of TNBC.

Promoting Apoptosis, a Promising Way to Treat Breast Cancer With Natural Products: A Comprehensive Review

“…Li et al (2017b) demonstrated that the mechanism of apoptosis induced by liriodenine in MCF-7 cells inhibited the expression of Bcl-2, cyclin D1, and vascular endothelial growth factor (VEGF) and upregulated the level of p53. As shown in the study by Liang et al (2021), resveratrol can facilitate TNBC cell apoptosis via the p53mediated pathway. In 2021, a study by Vazhappilly et al indicated that catechol could inhibit proliferation and result in apoptosis in MCF-7 cells by activating p53, inhibiting of regulatory proteins such as DNMT1, P-BRCA1, Mcl-1, and PDCD6, and increasing the Bax/Bcl-2 ratio.…”

Beneficial Oxidative Stress-Related trans-Resveratrol Effects in the Treatment and Prevention of Breast Cancer

“…All these mechanisms are related to the activation of the p53 oncosuppressor, a transcription factor involved in cell cycle regulation and apoptosis [111]. This was recently confirmed by Liang and colleagues, who demonstrated through RNA sequencing that genes affected by resveratrol treatment in MDA-MB-231 cells were mainly involved in apoptosis and the p53 signaling pathway [82].…”

“…Reduced angiogenesis [81,82] Phosphorylation or acetylation of p53 at the level of the serine residue 15…”

Targeting regulated cell death (RCD) with small-molecule compounds in triple-negative breast cancer: a revisited perspective from molecular mechanisms to targeted therapies

“…In contrast, ruthenium (II)/allopurinol complex binds to tumor cells to cause DNA damage and upregulate p53 protein, then causing the overexpression of bim, beclin-1 and caspase-3, and ultimately induced cell apoptosis [ 121 ]. Additional small-molecule compounds target p53 protein to induce apoptosis in TNBC cells [ 122 – 126 ] (Table 1 ).…”