Rhus coriaria induces senescence and autophagic cell death in breast cancer cells through a mechanism involving p38 and ERK1/2 activation.
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.
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Hussain
H
El Hasasna
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Khawlah
K
Athamneh
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Halima
H
Al Samri
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Noushad
N
Karuvantevida
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Yusra
Y
Al Dhaheri
Department of Chemistry, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Soleiman
S
Hisaindee
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Gaber
G
Ramadan
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Nedaa
N
Al Tamimi
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Synan
S
AbuQamar
Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, P.O. Box: 2713, Doha, Qatar.
Ali
A
Eid
Department of Biology, College of Science, United Arab Emirates University, Al-Ain, P.O. Box 15551, United Arab Emirates.
Rabah
R
Iratni
D001343:Autophagy / Q000502:physiology*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology*; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D029045:Rhus / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D048051:p38 Mitogen-Activated Protein Kinases