Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca 2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells.
Pawan FarisAgnese RumoloGiorgia PellavioMatteo TanziMauro VismaraRoberto Berra-RomaniAndrea GerbinoSalvatore CoralloPaolo PedrazzoliUmberto LaforenzaDaniela MontagnaFrancesco MocciaPublished in: Cell death discovery (2023)
Colorectal carcinoma (CRC) represents the fourth most common cancer worldwide and is the third most common cause of malignancy-associated mortality. Distant metastases to the liver and lungs are the main drivers of CRC-dependent death. Pro-oxidant therapies, which halt disease progression by exacerbating oxidative stress, represent an antitumour strategy that is currently exploited by chemotherapy and ionizing radiation. A more selective strategy to therapeutically exploit reactive oxygen species (ROS) signaling would consist in targeting a redox sensor that is up-regulated in metastatic cells and is tightly coupled to the stimulation of cancer cell death programs. The non-selective cation channel, Transient Receptor Potential Ankyrin 1 (TRPA1), serves as a sensor of the cellular redox state, being activated to promote extracellular Ca 2+ entry by an increase in oxidative stress. Recent work demonstrated that TRPA1 channel protein is up-regulated in several cancer types and that TRPA1-mediated Ca 2+ signals can either engage an antiapoptotic pro-survival signaling pathway or to promote mitochondrial Ca 2+ dysfunction and apoptosis. Herein, we sought to assess for the first time the outcome of TRPA1 activation by ROS on primary cultures of metastatic colorectal carcinoma (mCRC cells). We found that TRPA1 channel protein is up-regulated and mediates enhanced hydrogen peroxide (H 2 O 2 )-induced Ca 2+ entry in mCRC cells as compared to non-neoplastic control cells. The lipid peroxidation product 4-hydroxynonenal (4-HNE) is the main ROS responsible for TRPA1 activation upon mCRC cell exposure to oxidative stress. TRPA1-mediated Ca 2+ entry in response to H 2 O 2 and 4-HNE results in mitochondrial Ca 2+ overload, followed by mitochondrial depolarization and caspase-3/7 activation. Therefore, targeting TRPA1 could represent an alternative strategy to eradicate metastatic CRC by enhancing its sensitivity to oxidative stress.
Keyphrases
- induced apoptosis
- oxidative stress
- cell death
- cell cycle arrest
- diabetic rats
- reactive oxygen species
- endoplasmic reticulum stress
- signaling pathway
- dna damage
- hydrogen peroxide
- squamous cell carcinoma
- ischemia reperfusion injury
- small cell lung cancer
- pi k akt
- papillary thyroid
- transcription factor
- protein kinase
- coronary artery disease
- single cell
- public health
- radiation therapy
- high glucose
- stem cells
- epithelial mesenchymal transition
- endothelial cells
- cardiovascular disease
- mesenchymal stem cells
- cardiovascular events
- locally advanced
- cell proliferation
- climate change
- cell therapy
- cerebral ischemia
- heat shock protein