Concomitant Inhibition of IRE1α/XBP1 Axis of UPR and PARP: A Promising Therapeutic Approach against c-Myc and Gammaherpesvirus-Driven B-Cell Lymphomas

被引：4

作者：

Benedetti, Rossella ^{[1
]}

Arena, Andrea ^{[1
]}

Romeo, Maria Anele ^{[1
]}

Gilardini Montani, Maria Saveria ^{[1
]}

Gonnella, Roberta ^{[1
]}

Santarelli, Roberta ^{[1
]}

Trivedi, Pankaj ^{[1
]}

Cirone, Mara ^{[1
]}

机构：

[1] Sapienza Univ Rome, Dept Expt Med, Viale Regina Elena 324, I-00161 Rome, Italy

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2022年 / 23卷 / 16期

关键词：

Burkitt lymphoma; UPR; IRE1; alpha/XBP1; c-Myc; DDR; BRCA-1; CANCER-CELLS; EXPRESSION; MECHANISMS; RESISTANCE; LATENCY;

D O I：

10.3390/ijms23169113

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

It is emerging that targeting the adaptive functions of Unfolded Protein Response (UPR) may represent a promising anti-cancer therapeutic approach. This is particularly relevant for B-cell lymphomas, characterized by a high level of constitutive stress due to high c-Myc expression. In this study, we found that IRE1 alpha/XBP1 axis inhibition exerted a stronger cytotoxic effect compared to the inhibition of the other two UPR sensors, namely PERK and ATF6, in Burkitt lymphoma (BL) cells, in correlation with c-Myc downregulation. Interestingly, such an effect was more evident in Epstein-Barr virus (EBV)-negative BL cells or those cells expressing type I latency compared to type III latency BL cells. The other interesting finding of this study was that the inhibition of IRE1 alpha/XBP1 downregulated BRCA-1 and RAD51 and potentiated the cytotoxicity of PARP inhibitor AZD2661 against BL cells and also against Primary Effusion Lymphoma (PEL), another aggressive B-cell lymphoma driven by c-Myc and associated with gammaherpesvirus infection. These results suggest that combining the inhibition of UPR sensors, particularly IRE1 alpha/XBP1 axis, and molecules involved in DDR, such as PARP, could offer a new therapeutic opportunity for treating aggressive B-cell lymphomas such as BL and PEL.

引用

页数：13