Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells.
Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells.
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DOI：
10.3390/biomedicines10040731
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发表时间：
2022-03-22
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
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多发性骨髓瘤（MM）和原发性渗出性淋巴瘤（PEL）是侵袭性血液系统癌症，需要寻找新的和更有效的治疗方法。这两种癌症都过表达c-Myc，并且高度依赖于这种原癌基因才能生存。尽管c-Myc抑制已显示可降低PEL和MM存活率，但导致这种效应的潜在机制尚未完全阐明。在这项研究中，通过药理学抑制和沉默，我们表明，c-Myc站在UPR和DDR之间的十字路口。事实上，它通过IRE 1 α/XBP 1轴在维持UPR的促生存功能中发挥关键作用，并维持MM和PEL细胞中DDR分子如RAD 51和BRCA 1的表达水平。此外，我们发现c-Myc与IRE 1 α/XBP 1轴建立了相互作用，IRE 1 α/XBP 1轴的抑制下调c-Myc，使UPR偏向细胞死亡并增强DNA损伤。总之，这项研究揭示了导致c-Myc抑制的细胞毒性作用的分子机制的新见解，并加强了这样一种观点，即其靶向可能是一种有希望的治疗方法，尽管不同的癌症，但有一些相似之处，包括c-Myc过表达，组成性ER应激和对当前化疗的反应差。
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.
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