Rhus coriaria increases protein ubiquitination, proteasomal degradation and triggers non-canonical Beclin-1-independent autophagy and apoptotic cell death in colon cancer cells

Khawlah Athamneh,Halima Al Samri,Kholoud Arafat,Hussain El Hasasna,Samir Attoub,Yusra Al Dhaheri,Ali Eid,Asma Al Rashedi,Synan Abuqamar,Nehla Benhalilou,Rabah Iratni

doi:10.1038/s41598-017-11202-3

Khawlah Athamneh, Halima Al Samri + Show 9 more

Open Access

https://doi.org/10.1038/s41598-017-11202-3

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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.

Highlights

Cancer therapies have witnessed great advances in the recent past; cancer continues to be a leading cause of death, with colorectal cancer being the fourth cause of cancer-related deaths[1]
In our recently published study, we showed that Rhus coriaria extract could promote autophagy[14] and suppress angiogenesis, metastasis and tumor growth of highly invasive and metastatic breast cancer[15]
Rats fed with doses up to 1 g/kg of lyophilized extract showed no signs of toxicity or mortality[36]

Summary

Introduction

Cancer therapies have witnessed great advances in the recent past; cancer continues to be a leading cause of death, with colorectal cancer being the fourth cause of cancer-related deaths[1]. Colorectal cancer affects both sexes with poor survival rate once it metastasizes[1]. Phytochemicals, which are plant derived compounds that have been increasingly utilized as anti-cancer drugs due to accumulated evidences that support their potential[2]. More commonly known as sumac, belongs to the Anacardiaceae family. We showed for the first time, that RCE possesses anti-cancer effects against human triple-negative breast cancer cells. This autophagy appears to be the main mechanism of RCE-induced cell death[14, 15]

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