@article{4f0a79b14edf42eb93a613a672971375,
title = "Rhus coriaria increases protein ubiquitination, proteasomal degradation and triggers non-canonical Beclin-1-independent autophagy and apoptotic cell death in colon cancer cells",
abstract = "Colorectal cancer is the fourth leading cause of cancer-related deaths worldwide. Here, we investigated the anticancer effect of Rhus coriaria extract (RCE) on HT-29 and Caco-2 human colorectal cancer cells. We found that RCE significantly inhibited the viability and colony growth of colon cancer cells. Moreover, RCE induced Beclin-1-independent autophagy and subsequent caspase-7-dependent apoptosis. Blocking of autophagy by chloroquine significantly reduced RCE-induced cell death, while blocking of apoptosis had no effect on RCE-induced cell death. Mechanistically, RCE inactivated the AKT/mTOR pathway by promoting the proteasome-dependent degradation of both proteins. Strikingly, we also found that RCE targeted Beclin-1, p53 and procaspase-3 to degradation. Proteasome inhibition by MG-132 not only restored these proteins to level comparable to control cells, but also reduced RCE-induced cell death and blocked the activation of autophagy and apoptosis. The proteasomal degradation of mTOR, which occurred only 3 hours post-RCE treatment was concomitant with an overall increase in the level of ubiquitinated proteins and translated stimulation of proteolysis by the proteasome. Our findings demonstrate that Rhus coriaria possesses strong anti-colon cancer activity through stimulation of proteolysis as well as induction of autophagic and apoptotic cell death, making it a potential and valuable source of novel therapeutic cancer drug.",
author = "Khawlah Athamneh and Hasasna, {Hussain El} and Samri, {Halima Al} and Samir Attoub and Kholoud Arafat and Nehla Benhalilou and Rashedi, {Asma Al} and Dhaheri, {Yusra Al} and Synan Abuqamar and Ali Eid and Rabah Iratni",
note = "Funding Information: Apoptosis and autophagy are considered two different events; cross-talk between autophagy and apoptosis exists and the intricate interplay between these two mechanisms is a big challenge for cancer treatment. Autophagy seems to play a role in cancer cell survival and cell death. It contributes to cytoprotective events that help cancer cells to survive and to protect cells from apoptosis48. In other circumstances, autophagy can stimulate a pro-death signal pathway in cancer cells. Moreover, under some situations, apoptosis and autophagy can exert synergetic effects, whereas in other conditions autophagy can be triggered only when apoptosis is suppressed48. Hence, the question whether autophagy elicits or inhibits apoptosis may depend upon the cell type, nature and duration of stimulus49. Here we showed that although apoptosis is activated in response to RCE, it does not constitute the main mechanism of cell death and cell death occurs mainly through PCD-II probably as result of excessive autophagy. This claim is supported by several evidences. First, we showed that autophagy preceded apoptosis. Indeed, while activation of autophagy occurred as early as 12 hours and reduced cell viability was observed already after 24h post-RCE treatment, apoptosis on the other hand was apparent after 48hours, revealed by caspase-7 activation and PARP cleavage. Moreover, chemical inhibition of autophagy by CQ abrogated RCE-induced cell death while inhibition of apoptosis by the pan-caspase inhibitor had no effect on cell death. Our results here revealed that even though caspase-3 is markedly depleted in RCE-treated HT-29 cells, due to its proteasome-dependent degradation, the mechanism for apoptosis is still functional. Indeed, we showed that these cells were able to induce apoptosis through an alternate caspase-7 dependent pathway. Similarly induction of caspase-7-dependent autophagy was observed in caspase-3 deficient breast cancer cells when treated with tyrylpy-rone derivative (SPD), a plant-derived pharmacologically active compound extracted from Goniothalamus sp.50. We believe that cell death through activation of apoptosis, although minimal, comes as secondary response due to increased intracellular stresses and therefore accumulation of cellular damage due to longer exposure of the cells to RCE. Publisher Copyright: {\textcopyright} 2017 The Author(s).",
year = "2017",
month = dec,
day = "1",
doi = "10.1038/s41598-017-11202-3",
language = "British English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}
