Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells
Novel Interleukin-6 Inducible Gene PDZ-Binding Kinase Promotes Tumor Growth of Multiple Myeloma Cells
复制标题
DOI：
10.1089/jir.2020.0111
复制
发表时间：
2020-07
影响因子：
2.3
通讯作者：
Akinobu Ota;I. Hanamura;S. Karnan;Shingo Inaguma;Norio Takei;Vu Quang Lam;Shohei Mizuno;Jo Kanasugi;M. Wahiduzzaman;Md. Lutfur Rahman;T. Hyodo;H. Konishi;S. Tsuzuki;H. Ikeda;A. Takami;Y. Hosokawa
中科院分区：
文献类型：
--
作者：
Akinobu Ota;I. Hanamura;S. Karnan;Shingo Inaguma;Norio Takei;Vu Quang Lam;Shohei Mizuno;Jo Kanasugi;M. Wahiduzzaman;Md. Lutfur Rahman;T. Hyodo;H. Konishi;S. Tsuzuki;H. Ikeda;A. Takami;Y. Hosokawa
多发性骨髓瘤（MM）仍然是一个难治性血液恶性肿瘤，尽管最近的进展，抗MM药物。在这里，我们展示了PDZ结合激酶（PBK）在MM肿瘤生长中的作用。我们发现，白细胞介素-6（IL-6）容易增加PI 3 K的表达。Kaplan-Meier分析显示，PI 3 K高表达的MM患者的生存期明显短于PI 3 K中/低表达的MM患者。PI 3 K的敲除显著抑制MM细胞中的体内肿瘤生长，而PI 3 K从天冬酰胺变为丝氨酸取代（rs3779620）的基因组编辑轻微抑制肿瘤形成。从机制上讲，PI 3 K的丢失增加了凋亡细胞的数量，伴随着Stat 3磷酸化水平和caspase活性的降低。一种新的PI 3 K抑制剂OTS 514显著降低了KMS-11衍生的肿瘤生长。这些发现突出了PBK在骨髓瘤肿瘤生长中的新的致癌作用，并且其可能是MM患者治疗的新的治疗靶点。
Multiple myeloma (MM) remains an intractable hematological malignancy, despite recent advances in anti-MM drugs. Here, we show that role of PDZ binding kinase (PBK) in MM tumor growth. We identified that interleukin-6 (IL-6) readily increases PBK expression. Kaplan–Meier analysis showed that the MM patients with higher expression of PBK have a significant shorter survival time compared with those with moderate/lower expression of PBK. Knockout of PBK dramatically suppressed in vivo tumor growth in MM cells, while genome editing of PBK changing from asparagine to serine substitution (rs3779620) slightly suppresses the tumor formation. Mechanistically, loss of PBK increased the number of apoptotic cells with concomitant decrease in the phosphorylation level of Stat3 as well as caspase activities. A novel PBK inhibitor OTS514 significantly decreased KMS-11-derived tumor growth. These findings highlight the novel oncogenic role of PBK in tumor growth of myeloma, and it might be a novel therapeutic target for the treatment of patients with MM.