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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.

SUBMITTER: Athamneh K

PROVIDER: S-EPMC5599689 | biostudies-other | 2017 Sep

REPOSITORIES: biostudies-other

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

Athamneh Khawlah K Hasasna Hussain El HE Samri Halima Al HA Attoub Samir S Arafat Kholoud K Benhalilou Nehla N Rashedi Asma Al AA Dhaheri Yusra Al YA AbuQamar Synan S Eid Ali A Iratni Rabah R

Scientific reports 20170914 1

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 blockin ...[more]

PMID: 28912474

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Project description:Epstein-Barr virus (EBV) nuclear oncoprotein EBNA3C is essential for B-cell transformation and development of several B-cell lymphomas particularly those are generated in an immuno-compromised background. EBNA3C recruits ubiquitin-proteasome machinery for deregulating multiple cellular oncoproteins and tumor suppressor proteins. Although EBNA3C is found to be ubiquitinated at its N-terminal region and interacts with 20S proteasome, the viral protein is surprisingly stable in growing B-lymphocytes. EBNA3C can also circumvent autophagy-lysosomal mediated protein degradation and subsequent antigen presentation for T-cell recognition. Recently, we have shown that EBNA3C enhances autophagy, which serve as a prerequisite for B-cell survival particularly under growth deprivation conditions. We now demonstrate that proteasomal inhibition by MG132 induces EBNA3C degradation both in EBV transformed B-lymphocytes and ectopic-expression systems. Interestingly, MG132 treatment promotes degradation of two EBNA3 family oncoproteins-EBNA3A and EBNA3C, but not the viral tumor suppressor protein EBNA3B. EBNA3C degradation induced by proteasomal inhibition is partially blocked when autophagy-lysosomal pathway is inhibited. In response to proteasomal inhibition, EBNA3C is predominantly K63-linked polyubiquitinated, colocalized with the autophagy-lysosomal fraction in the cytoplasm and participated within p62-LC3B complex, which facilitates autophagy-mediated degradation. We further show that the degradation signal is present at the first 50 residues of the N-terminal region of EBNA3C. Proteasomal inhibition reduces the colony formation ability of this important viral oncoprotein, induces apoptotic cell death and increases transcriptional activation of both latent and lytic gene expression which further promotes viral reactivation from EBV transformed B-lymphocytes. Altogether, this study offers rationale to use proteasome inhibitors as potential therapeutic strategy against multiple EBV associated B-cell lymphomas, where EBNA3C is expressed.

Project description:Macroautophagy/autophagy-related proteins regulate infectious and inflammatory diseases in autophagy-dependent or -independent manner. However, the role of a newly identified mammalian-specific autophagy protein-BECN2 (beclin 2) in innate immune regulation is largely unknown. Here we showed that loss of BECN2 enhanced the activities of NLRP3, AIM2, NLRP1, and NLRC4 inflammasomes upon ligand stimulations. Mechanistically, BECN2 interacted with inflammasome sensors and mediated their degradation through a ULK1- and ATG9A-dependent, but BECN1-WIPI2-ATG16L1-LC3-independent, non-canonical autophagic pathway. BECN2 recruited inflammasome sensors on ATG9A+ vesicles to form a complex (BECN2-ATG9A-sensors) upon ULK1 activation. Three soluble NSF attachment protein receptor (SNARE) proteins (SEC22A, STX5, and STX6) were further shown to mediate the BECN2-ATG9A-dependent inflammasome sensor degradation. Loss of BECN2 promoted alum-induced peritonitis, which could be rescued by the ablation of CASP1 in Becn2-deficient mice. Hence, BECN2 negatively regulated inflammasome activation to control inflammation, serving as a potential therapeutic target for the treatment of infectious and inflammatory diseases.Abbreviations: AIM2: absent in melanoma 2; ATG: autophagy related; BECN1: beclin 1; BMDC: bone marrow-derived dendritic cells; BMDM: bone marrow-derived macrophages; CASP1: caspase 1; CQ: chloroquine; gMDSC: granulocytic myeloid-derived suppressor cells; IL: interleukin; LPS: lipopolysaccharide; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; mMDSC: monocytic myeloid-derived suppressor cells; NLRC4: NLR family CARD domain containing 4; NLRP1: NLR family pyrin domain containing 1; NLRP3: NLR family pyrin domain containing 3; PECs: peritoneal exudate cells; PYCARD/ASC: apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; SNAREs: soluble NSF attachment protein receptors; STX5: syntaxin 5; STX6: syntaxin 6; ULK1: unc-51 like autophagy activating kinase 1; WIPI: WD repeat domain, phosphoinositide interacting.

Dataset Information

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

Publications

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

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