Rhus coriaria induces senescence and autophagic cell death in breast cancer cells through a mechanism involving p38 and ERK1/2 activation

Abstract

Here, we investigated the anticancer effect of Rhus coriaria on three breast cancer cell lines. We demonstrated that Rhus coriaria ethanolic extract (RCE) inhibits the proliferation of these cell lines in a time- and concentration-dependent manner. RCE induced senescence and cell cycle arrest at G1 phase. These changes were concomitant with upregulation of p21, downregulation of cyclin D1, p27, PCNA, c-myc, phospho-RB and expression of senescence-associated β-galactosidase activity. No proliferative recovery was detected after RCE removal. Annexin V staining and PARP cleavage analysis revealed a minimal induction of apoptosis in MDA-MB-231 cells. Electron microscopy revealed the presence of autophagic vacuoles in RCE-treated cells. Interestingly, blocking autophagy by 3-methyladenine (3-MA) or chloroquine (CQ) reduced RCE-induced cell death and senescence. RCE was also found to activate p38 and ERK1/2 signaling pathways which coincided with induction of autophagy. Furthermore, we found that while both autophagy inhibitors abolished p38 phosphorylation, only CQ led to significant decrease in pERK1/2. Finally, RCE induced DNA damage and reduced mutant p53, two events that preceded autophagy. Our findings provide strong evidence that R. coriaria possesses strong anti-breast cancer activity through induction of senescence and autophagic cell death, making it a promising alternative or adjunct therapeutic candidate against breast cancer.

Anticancer, Antiproliferative, Lysosomal and Lactate Dehydrogenase Inhibitory Effects of Fruit Extracts from Sumac (Rhus coriaria L.) on Human Lung Cancer Cells

“…When the concentration of the sumac extract increased, the number of live cells decreased. Our results were consistent with the previously anticancer studies with sumac (1,9,24), the anticancer and growth inhibitory effects of the extracts may be due to the fact that rich secondary metabolites components of the R. coriaria L., as described previously (12,25,26).…”

Autophagy Protects from Raddeanin A‐Induced Apoptosis in SGC‐7901 Human Gastric Cancer Cells

“…As one of the most important intracellular pathways, MAPK pathway is frequently activated in a number of cancers and is responsible for the resistance of cell growth, autophagy [9], apoptosis [8, 23], metabolism, and invasion [24]. In the present research, it is discovered that RA could effectively activate p38 MAPK pathway (Figure 2(d)).…”

“…p38 MAPK pathway has been proved to be associated with induction of apoptosis [7, 8] and autophagy [9]. We therefore speculated that RA might induce apoptosis and autophagy in SGC-7901 cells by suppressing the p38 MAPK signaling pathway.…”

Phytochemical Diversity and Pharmacological Properties of Rhus coriaria

“…El Hasasna et al. (2015, 2016) reported that the ethanolic extract obtained from Lebanese R. coriaria showed interesting antiproliferative activity against T47D, MCF‐7 and MDA‐MB‐231 breast cancer cells. The results showed that T47D and MDA‐MB‐231 cells were more sensitive to the investigated ethanolic extract than MCF‐7 cell lines.…”