Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib.
Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib.
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DOI：
10.3390/ijms21176314
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发表时间：
2020-08-31
影响因子：
5.6
通讯作者：
Tamura S
中科院分区：
文献类型：
--
作者：
Yamashita Y;Morita S;Hosoi H;Kobata H;Kishimoto S;Ishibashi T;Mishima H;Kinoshita A;Backes BJ;Yoshiura KI;Papa FR;Sonoki T;Tamura S
背景：肌醇需要酶1α(IRE1α)与蛋白激酶R样内质网状激酶(PERK)一起是未折叠蛋白反应(UPR)的主要调节因子。最近，针对IRE1KIRA6的α抑制剂--激酶抑制核糖核酸酶衰减器6(KIRA6)被证明对多发性骨髓瘤(MM)有良好的治疗效果。回避临床翻译，MM患者的详细UPR表型以及KIRA8在MM中如何发挥作用的机制仍不清楚。方法：我们鉴定了新诊断的MM患者骨髓中的UPR表型，然后在人MM细胞中分析了KIRA8和食品和药物管理局批准的药物尼洛替尼可能的抗肿瘤机制，我们最近发现尼洛替尼对IRE1α活性有很强的抑制作用。结果：我们阐明了在骨髓瘤患者中，在骨髓瘤患者中，骨髓瘤患者在骨髓瘤PERK通路上诱导适应性α标记的优势。在人骨髓瘤细胞中，KIRA8降低细胞存活率，诱导细胞凋亡，同时诱导C/EBP同源蛋白(CHOP)；它与Bortezomib联合使用显示出比单独使用KIRA8更强的抗骨髓瘤作用。与KIRA8相比，尼洛替尼具有类似的作用。RNA测序证实Polo-like kinase2(PLK2)是KIRA8抑制基因。IRE1α过表达诱导PLK2表达，KIRA8抑制PLK2表达。KIRA8和PLK2抑制通过诱导细胞凋亡和调节细胞增殖发挥抗骨髓瘤作用。结论：MM患者体内存在适应性IRE1α的优势激活，KIRA8和尼洛替尼均具有抗骨髓瘤作用，而硼替佐米可增强其抗骨髓瘤作用。适应性IRE1、α信号和PLK2可能成为MM的潜在治疗靶点和生物标志物。
Background: Inositol-requiring enzyme 1α (IRE1α), along with protein kinase R-like endoplasmic reticulum kinase (PERK), is a principal regulator of the unfolded protein response (UPR). Recently, the ‘mono’-specific IRE1α inhibitor, kinase-inhibiting RNase attenuator 6 (KIRA6), demonstrated a promising effect against multiple myeloma (MM). Side-stepping the clinical translation, a detailed UPR phenotype in patients with MM and the mechanisms of how KIRA8 works in MM remains unclear. Methods: We characterized UPR phenotypes in the bone marrow of patients with newly diagnosed MM. Then, in human MM cells we analyzed the possible anti-tumor mechanisms of KIRA8 and a Food and Drug Administration (FDA)-approved drug, nilotinib, which we recently identified as having a strong inhibitory effect against IRE1α activity. Finally, we performed an RNA-sequence analysis to detect key IRE1α-related molecules against MM. Results: We illustrated the dominant induction of adaptive UPR markers under IRE1α over the PERK pathway in patients with MM. In human MM cells, KIRA8 decreased cell viability and induced apoptosis, along with the induction of C/EBP homologous protein (CHOP); its combination with bortezomib exhibited more anti-myeloma effects than KIRA8 alone. Nilotinib exerted a similar effect compared with KIRA8. RNA-sequencing identified Polo-like kinase 2 (PLK2) as a KIRA8-suppressed gene. Specifically, the IRE1α overexpression induced PLK2 expression, which was decreased by KIRA8. KIRA8 and PLK2 inhibition exerted anti-myeloma effects with apoptosis induction and the regulation of cell proliferation. Finally, PLK2 was pathologically confirmed to be highly expressed in patients with MM. Conclusion: Dominant activation of adaptive IRE1α was established in patients with MM. Both KIRA8 and nilotinib exhibited anti-myeloma effects, which were enhanced by bortezomib. Adaptive IRE1α signaling and PLK2 could be potential therapeutic targets and biomarkers in MM.
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影响因子：
29
作者：
Lerner AG;Upton JP;Praveen PV;Ghosh R;Nakagawa Y;Igbaria A;Shen S;Nguyen V;Backes BJ;Heiman M;Heintz N;Greengard P;Hui S;Tang Q;Trusina A;Oakes SA;Papa FR
通讯作者：
Papa FR
影响因子：
11.4
作者：
Chim CS;Kumar SK;Orlowski RZ;Cook G;Richardson PG;Gertz MA;Giralt S;Mateos MV;Leleu X;Anderson KC
通讯作者：
Anderson KC
影响因子：
--
作者：
Newbatt, Yvette;Hardcastle, Anthea;van Montfort, Rob L. M.
通讯作者：
van Montfort, Rob L. M.
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Bettigole SE;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
5.8
作者：
Nikesitch N;Lee JM;Ling S;Roberts TL
通讯作者：
Roberts TL