IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response
IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that e...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2116844 |
| _version_ | 1818495753688973312 |
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| author | Adriana Martinez-Turtos Rachel Paul Manuel Grima-Reyes Hussein Issaoui Adrien Krug Rana Mhaidly Jozef P. Bossowski Johanna Chiche Sandrine Marchetti Els Verhoeyen Eric Chevet Jean-Ehrland Ricci |
| author_facet | Adriana Martinez-Turtos Rachel Paul Manuel Grima-Reyes Hussein Issaoui Adrien Krug Rana Mhaidly Jozef P. Bossowski Johanna Chiche Sandrine Marchetti Els Verhoeyen Eric Chevet Jean-Ehrland Ricci |
| author_sort | Adriana Martinez-Turtos |
| collection | DOAJ |
| description | IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α. |
| first_indexed | 2024-12-10T18:24:55Z |
| format | Article |
| id | doaj.art-a17f8333685a4354820bb0d127341553 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-10T18:24:55Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-a17f8333685a4354820bb0d1273415532022-12-22T01:38:06ZengTaylor & Francis GroupOncoImmunology2162-402X2022-12-0111110.1080/2162402X.2022.2116844IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune responseAdriana Martinez-Turtos0Rachel Paul1Manuel Grima-Reyes2Hussein Issaoui3Adrien Krug4Rana Mhaidly5Jozef P. Bossowski6Johanna Chiche7Sandrine Marchetti8Els Verhoeyen9Eric Chevet10Jean-Ehrland Ricci11C3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceInserm U1242, Université de Rennes, Rennes, FranceC3M, INSERM, Université Côte d’Azur, Nice, FranceIRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2116844CancerUPRIRE1αXBP1sRIDDanti-cancer immunosurveillance |
| spellingShingle | Adriana Martinez-Turtos Rachel Paul Manuel Grima-Reyes Hussein Issaoui Adrien Krug Rana Mhaidly Jozef P. Bossowski Johanna Chiche Sandrine Marchetti Els Verhoeyen Eric Chevet Jean-Ehrland Ricci IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response OncoImmunology Cancer UPR IRE1α XBP1s RIDD anti-cancer immunosurveillance |
| title | IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response |
| title_full | IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response |
| title_fullStr | IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response |
| title_full_unstemmed | IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response |
| title_short | IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response |
| title_sort | ire1α overexpression in malignant cells limits tumor progression by inducing an anti cancer immune response |
| topic | Cancer UPR IRE1α XBP1s RIDD anti-cancer immunosurveillance |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2116844 |
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