Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells
Abstract 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 b...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01530-x |
| _version_ | 1797789945238126592 |
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| author | Pawan Faris Agnese Rumolo Giorgia Pellavio Matteo Tanzi Mauro Vismara Roberto Berra-Romani Andrea Gerbino Salvatore Corallo Paolo Pedrazzoli Umberto Laforenza Daniela Montagna Francesco Moccia |
| author_facet | Pawan Faris Agnese Rumolo Giorgia Pellavio Matteo Tanzi Mauro Vismara Roberto Berra-Romani Andrea Gerbino Salvatore Corallo Paolo Pedrazzoli Umberto Laforenza Daniela Montagna Francesco Moccia |
| author_sort | Pawan Faris |
| collection | DOAJ |
| description | Abstract 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 Ca2+ 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 Ca2+ signals can either engage an antiapoptotic pro-survival signaling pathway or to promote mitochondrial Ca2+ 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 (H2O2)-induced Ca2+ 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 Ca2+ entry in response to H2O2 and 4-HNE results in mitochondrial Ca2+ 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. |
| first_indexed | 2024-03-13T01:57:52Z |
| format | Article |
| id | doaj.art-ec3c7131d39a44beb21ad7dc3b05cf0b |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-13T01:57:52Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-ec3c7131d39a44beb21ad7dc3b05cf0b2023-07-02T11:07:13ZengNature Publishing GroupCell Death Discovery2058-77162023-07-019111010.1038/s41420-023-01530-xTransient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cellsPawan Faris0Agnese Rumolo1Giorgia Pellavio2Matteo Tanzi3Mauro Vismara4Roberto Berra-Romani5Andrea Gerbino6Salvatore Corallo7Paolo Pedrazzoli8Umberto Laforenza9Daniela Montagna10Francesco Moccia11Department of Biology and Biotechnology “Lazzaro Spallanzani”, University of PaviaFoundation IRCCS Policlinico San Matteo, Laboratory of Immunology TransplantationDepartment of Molecular Medicine, University of PaviaFoundation IRCCS Policlinico San Matteo, Laboratory of Immunology TransplantationDepartment of Biology and Biotechnology “Lazzaro Spallanzani”, University of PaviaDepartment of Biomedicine, School of Medicine, Benemérita Universidad Autónoma de PueblaDepartment of Biosciences, Biotechnologies and Environment, University of Bari Aldo MoroMedical Oncology, Foundation IRCCS Policlinico San MatteoMedical Oncology, Foundation IRCCS Policlinico San MatteoDepartment of Molecular Medicine, University of PaviaFoundation IRCCS Policlinico San Matteo, Laboratory of Immunology TransplantationDepartment of Biology and Biotechnology “Lazzaro Spallanzani”, University of PaviaAbstract 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 Ca2+ 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 Ca2+ signals can either engage an antiapoptotic pro-survival signaling pathway or to promote mitochondrial Ca2+ 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 (H2O2)-induced Ca2+ 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 Ca2+ entry in response to H2O2 and 4-HNE results in mitochondrial Ca2+ 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.https://doi.org/10.1038/s41420-023-01530-x |
| spellingShingle | Pawan Faris Agnese Rumolo Giorgia Pellavio Matteo Tanzi Mauro Vismara Roberto Berra-Romani Andrea Gerbino Salvatore Corallo Paolo Pedrazzoli Umberto Laforenza Daniela Montagna Francesco Moccia Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells Cell Death Discovery |
| title | Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells |
| title_full | Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells |
| title_fullStr | Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells |
| title_full_unstemmed | Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells |
| title_short | Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells |
| title_sort | transient receptor potential ankyrin 1 trpa1 mediates reactive oxygen species induced ca2 entry mitochondrial dysfunction and caspase 3 7 activation in primary cultures of metastatic colorectal carcinoma cells |
| url | https://doi.org/10.1038/s41420-023-01530-x |
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