Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells
Multiple myeloma (MM) and primary effusion lymphoma (PEL) are aggressive hematological cancers, for which the search for new and more effective therapies is needed. Both cancers overexpress c-Myc and are highly dependent on this proto-oncogene for their survival. Although c-Myc inhibition has been s...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/4/731 |
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| author | Andrea Arena Maria Anele Romeo Rossella Benedetti Maria Saveria Gilardini Montani Mara Cirone |
| author_facet | Andrea Arena Maria Anele Romeo Rossella Benedetti Maria Saveria Gilardini Montani Mara Cirone |
| author_sort | Andrea Arena |
| collection | DOAJ |
| description | Multiple myeloma (MM) and primary effusion lymphoma (PEL) are aggressive hematological cancers, for which the search for new and more effective therapies is needed. Both cancers overexpress c-Myc and are highly dependent on this proto-oncogene for their survival. Although c-Myc inhibition has been shown to reduce PEL and MM survival, the underlying mechanisms leading to such an effect are not completely clarified. In this study, by pharmacologic inhibition and silencing, we show that c-Myc stands at the cross-road between UPR and DDR. Indeed, it plays a key role in maintaining the pro-survival function of UPR, through the IRE1α/XBP1 axis, and sustains the expression level of DDR molecules such as RAD51 and BRCA1 in MM and PEL cells. Moreover, we found that c-Myc establishes an interplay with the IRE1α/XBP1 axis whose inhibition downregulated c-Myc, skewed UPR towards cell death and enhanced DNA damage. In conclusion, this study unveils new insights into the molecular mechanisms leading to the cytotoxic effects of c-Myc inhibition and reinforces the idea that its targeting may be a promising therapeutic approach against MM and PEL that, although different cancers, share some similarities, including c-Myc overexpression, constitutive ER stress and poor response to current chemotherapies. |
| first_indexed | 2024-03-09T11:08:41Z |
| format | Article |
| id | doaj.art-fd882ce8d26446179395140feb0f588b |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T11:08:41Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-fd882ce8d26446179395140feb0f588b2023-12-01T00:52:28ZengMDPI AGBiomedicines2227-90592022-03-0110473110.3390/biomedicines10040731Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma CellsAndrea Arena0Maria Anele Romeo1Rossella Benedetti2Maria Saveria Gilardini Montani3Mara Cirone4Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, ItalyMultiple myeloma (MM) and primary effusion lymphoma (PEL) are aggressive hematological cancers, for which the search for new and more effective therapies is needed. Both cancers overexpress c-Myc and are highly dependent on this proto-oncogene for their survival. Although c-Myc inhibition has been shown to reduce PEL and MM survival, the underlying mechanisms leading to such an effect are not completely clarified. In this study, by pharmacologic inhibition and silencing, we show that c-Myc stands at the cross-road between UPR and DDR. Indeed, it plays a key role in maintaining the pro-survival function of UPR, through the IRE1α/XBP1 axis, and sustains the expression level of DDR molecules such as RAD51 and BRCA1 in MM and PEL cells. Moreover, we found that c-Myc establishes an interplay with the IRE1α/XBP1 axis whose inhibition downregulated c-Myc, skewed UPR towards cell death and enhanced DNA damage. In conclusion, this study unveils new insights into the molecular mechanisms leading to the cytotoxic effects of c-Myc inhibition and reinforces the idea that its targeting may be a promising therapeutic approach against MM and PEL that, although different cancers, share some similarities, including c-Myc overexpression, constitutive ER stress and poor response to current chemotherapies.https://www.mdpi.com/2227-9059/10/4/731multiple myeloma (MM)primary effusion lymphoma (PEL)c-MycIRE1 α/XBP1CHOPDDR |
| spellingShingle | Andrea Arena Maria Anele Romeo Rossella Benedetti Maria Saveria Gilardini Montani Mara Cirone Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells Biomedicines multiple myeloma (MM) primary effusion lymphoma (PEL) c-Myc IRE1 α/XBP1 CHOP DDR |
| title | Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells |
| title_full | Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells |
| title_fullStr | Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells |
| title_full_unstemmed | Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells |
| title_short | Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells |
| title_sort | targeting c myc unbalances upr towards cell death and impairs ddr in lymphoma and multiple myeloma cells |
| topic | multiple myeloma (MM) primary effusion lymphoma (PEL) c-Myc IRE1 α/XBP1 CHOP DDR |
| url | https://www.mdpi.com/2227-9059/10/4/731 |
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