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Published on: June 14, 2016
A High-Molecular-Weight Fraction of Planarian Mucus Triggers UPR-Linked Cell Death Pathway in Human Bronchioalveolar
Gaetana Gambino1, Gemma Marcelli1, Paola Iacopetti1
1Department of Clinical and Experimental Medicine, University of Pisa, Via Volta 4, 56126 Pisa, Italy.
Abstract:
Natural products remain a major source of anticancer agents, yet freshwater organisms are largely unexplored. Building on our previous evidence that planarian mucus exerts cytostatic and cytotoxic effects on cancer cells, we investigated the involvement of endoplasmic reticulum stress and unfolded protein response (UPR) pathways. Mucus-induced cytotoxicity is ROS-dependent and associated with depletion of intracellular reduced glutathione (GSH), not through inhibition of the System Xc- transporter but potentially associated with upregulation of CHAC1, a glutathione-degrading enzyme. Mucus fractionation based on molecular weight identified the high-molecular-weight crude fraction as the one containing the bioactive entity, reproducing the effects of whole mucus. Treatment with this fraction early activates the PERK-ATF4 branch of the UPR, which could be responsible for driving CHAC1 induction. Moreover, ATF4 enhances DDIT3 expression, and activates a compensatory NRF2-dependent antioxidant response. At a later stage mucus also activates the IRE1α-XBP1 axis, with no ATF6 involvement, indicating selective UPR engagement in response to oxidative and lipid stress. Overall, our data are consistent with a potential PERK-ATF4-CHAC1-GSH self-sustaining axis promoting oxidative stress that culminates in cell death, supporting the potential of planarian mucus as a source of pleiotropic bioactive compounds, although the molecular identity of the active component(s) remains still unresolved.
Insights
Planarian mucus exhibits anticancer properties by inducing oxidative stress and endoplasmic reticulum stress (ER stress) in cancer cells. This natural product shows potential for developing novel cancer therapies.
Area of Science:
- Biochemistry
- Cell Biology
- Natural Products Chemistry
Background:
- Natural products are vital sources of anticancer drugs, but freshwater organisms remain under-researched.
- Planarian mucus has demonstrated cytostatic and cytotoxic effects on cancer cells, prompting further investigation into its mechanisms.
Purpose of the Study:
- To investigate the role of endoplasmic reticulum stress (ER stress) and the unfolded protein response (UPR) in planarian mucus-induced cancer cell death.
- To identify the molecular pathways and components responsible for the anticancer effects of planarian mucus.
Main Methods:
- Cancer cell treatment with planarian mucus and its fractions.
- Analysis of reactive oxygen species (ROS) and glutathione (GSH) levels.
- Investigation of UPR pathways, including PERK, ATF4, IRE1α, XBP1, and ATF6.
- Gene expression analysis for CHAC1, DDIT3, and antioxidant response pathways.
Main Results:
- Mucus-induced cytotoxicity is dependent on ROS and leads to GSH depletion, potentially via CHAC1 upregulation.
- High-molecular-weight mucus fractions contain the bioactive compounds.
- Early UPR activation involves the PERK-ATF4 pathway, driving CHAC1 induction and activating NRF2-dependent antioxidant responses.
- Later UPR activation involves the IRE1α-XBP1 axis, suggesting selective stress response pathways.
Conclusions:
- Planarian mucus triggers a self-sustaining axis (PERK-ATF4-CHAC1-GSH) that promotes oxidative stress and cancer cell death.
- The findings support planarian mucus as a promising source of anticancer compounds, though the specific active molecules require further identification.
