Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma
Cisplatin (CDDP) is one of the principal chemotherapeutic agents used for the first-line treatment of many malignancies, including non-small cell lung carcinoma (NSCLC). Despite its use for over 40 years, its mechanism of action is not yet fully understood. Store-operated calcium entry (SOCE), the m...
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| Format: | Article |
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MDPI AG
2019-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/3/430 |
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| author | Roberta Gualdani Marie de Clippele Ikram Ratbi Philippe Gailly Nicolas Tajeddine |
| author_facet | Roberta Gualdani Marie de Clippele Ikram Ratbi Philippe Gailly Nicolas Tajeddine |
| author_sort | Roberta Gualdani |
| collection | DOAJ |
| description | Cisplatin (CDDP) is one of the principal chemotherapeutic agents used for the first-line treatment of many malignancies, including non-small cell lung carcinoma (NSCLC). Despite its use for over 40 years, its mechanism of action is not yet fully understood. Store-operated calcium entry (SOCE), the main pathway allowing Ca<sup>2+</sup> entry in non-excitable cells, is involved in tumorogenesis, cancer progression and chemoresistance. It has become an attractive target in cancer treatment. In this study, we showed that siRNA-mediated depletion of stromal interaction molecule 1 (STIM1) and transient receptor potential channel 1 (TRPC1), two players of the store-operated calcium entry, dramatically reduced CDDP cytotoxicity in NSCLC cells. This was associated with an inhibition of the DNA damage response (DDR) triggered by CDDP. Moreover, STIM1 depletion also reduced CDDP-dependent oxidative stress. In parallel, SOCE activation induced Ca<sup>2+</sup> entry into the mitochondria, a major source of reactive oxygen species (ROS) within the cell. This effect was highly decreased in STIM1-depleted cells. We then conclude that mitochondrial Ca<sup>2+</sup> peak associated to the SOCE contributes to CDDP-induced ROS production, DDR and subsequent apoptosis. To the best of our knowledge, this is the first time that it is shown that Ca<sup>2+</sup> signalling constitutes an initial step in CDDP-induced apoptosis. |
| first_indexed | 2024-03-12T07:19:57Z |
| format | Article |
| id | doaj.art-26ffa120c6f945c0a5472e671b2ca7b4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T07:19:57Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-26ffa120c6f945c0a5472e671b2ca7b42023-09-02T22:28:28ZengMDPI AGCancers2072-66942019-03-0111343010.3390/cancers11030430cancers11030430Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung CarcinomaRoberta Gualdani0Marie de Clippele1Ikram Ratbi2Philippe Gailly3Nicolas Tajeddine4Laboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels 1200, BelgiumLaboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels 1200, BelgiumLaboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels 1200, BelgiumLaboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels 1200, BelgiumLaboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels 1200, BelgiumCisplatin (CDDP) is one of the principal chemotherapeutic agents used for the first-line treatment of many malignancies, including non-small cell lung carcinoma (NSCLC). Despite its use for over 40 years, its mechanism of action is not yet fully understood. Store-operated calcium entry (SOCE), the main pathway allowing Ca<sup>2+</sup> entry in non-excitable cells, is involved in tumorogenesis, cancer progression and chemoresistance. It has become an attractive target in cancer treatment. In this study, we showed that siRNA-mediated depletion of stromal interaction molecule 1 (STIM1) and transient receptor potential channel 1 (TRPC1), two players of the store-operated calcium entry, dramatically reduced CDDP cytotoxicity in NSCLC cells. This was associated with an inhibition of the DNA damage response (DDR) triggered by CDDP. Moreover, STIM1 depletion also reduced CDDP-dependent oxidative stress. In parallel, SOCE activation induced Ca<sup>2+</sup> entry into the mitochondria, a major source of reactive oxygen species (ROS) within the cell. This effect was highly decreased in STIM1-depleted cells. We then conclude that mitochondrial Ca<sup>2+</sup> peak associated to the SOCE contributes to CDDP-induced ROS production, DDR and subsequent apoptosis. To the best of our knowledge, this is the first time that it is shown that Ca<sup>2+</sup> signalling constitutes an initial step in CDDP-induced apoptosis.https://www.mdpi.com/2072-6694/11/3/430store-operated calcium entrycisplatinapoptosisreactive oxygen speciesmitochondrial calciumnon-small cell lung carcinoma |
| spellingShingle | Roberta Gualdani Marie de Clippele Ikram Ratbi Philippe Gailly Nicolas Tajeddine Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma Cancers store-operated calcium entry cisplatin apoptosis reactive oxygen species mitochondrial calcium non-small cell lung carcinoma |
| title | Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma |
| title_full | Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma |
| title_fullStr | Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma |
| title_full_unstemmed | Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma |
| title_short | Store-Operated Calcium Entry Contributes to Cisplatin-Induced Cell Death in Non-Small Cell Lung Carcinoma |
| title_sort | store operated calcium entry contributes to cisplatin induced cell death in non small cell lung carcinoma |
| topic | store-operated calcium entry cisplatin apoptosis reactive oxygen species mitochondrial calcium non-small cell lung carcinoma |
| url | https://www.mdpi.com/2072-6694/11/3/430 |
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