Arena Andrea, Romeo Maria Anele, Benedetti Rossella, Gilardini Montani Maria Saveria, Cirone Mara
Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
Biomedicines. 2022 Mar 22;10(4):731. doi: 10.3390/biomedicines10040731.
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.
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，因此需要寻找新的更有效的治疗方法。这两种癌症均过度表达c-Myc，并且其生存高度依赖于这种原癌基因。尽管已证明抑制c-Myc可降低PEL和MM的生存率，但导致这种效应的潜在机制尚未完全阐明。在本研究中，通过药理学抑制和基因沉默，我们表明c-Myc处于未折叠蛋白反应（UPR）和DNA损伤反应（DDR）的交叉点。实际上，它通过IRE1α/XBP1轴在维持UPR的促生存功能中起关键作用，并维持MM和PEL细胞中DDR分子如RAD51和BRCA1的表达水平。此外，我们发现c-Myc与IRE1α/XBP1轴建立了相互作用，抑制该轴会下调c-Myc，使UPR偏向细胞死亡并增强DNA损伤。总之，本研究揭示了导致c-Myc抑制产生细胞毒性作用的分子机制的新见解，并强化了以下观点：靶向c-Myc可能是一种针对MM和PEL的有前景的治疗方法，这两种癌症虽然不同，但具有一些相似之处，包括c-Myc过表达、持续性内质网应激和对当前化疗反应不佳。
