Hoang Bao, Shi Yijiang, Frost Patrick J, Mysore Veena, Bardeleben Carolyne, Lichtenstein Alan
Department of Medicine, Hematology-Oncology Division, Greater Los Angeles VA Healthcare Center, UCLA Medical Center, Jonsson Comprehensive Cancer Center, Los Angeles, California.
Mol Cancer Res. 2016 Apr;14(4):397-407. doi: 10.1158/1541-7786.MCR-15-0422. Epub 2016 Feb 11.
To assess the role of the serum and glucocorticoid-regulated kinase (SGK) kinase in multiple myeloma, we ectopically expressed wild type or a phosphomimetic version of SGK into multiple myeloma cell lines. These cells were specifically resistant to the ER stress inducers tunicamycin, thapsigargin, and bortezomib. In contrast, there was no alteration of sensitivity to dexamethasone, serum starvation, or mTORC inhibitors. Mining of genomic data from a public database indicated that low baseline SGK expression in multiple myeloma patients correlated with enhanced ability to undergo a complete response to subsequent bortezomib treatment and a longer time to progression and overall survival following treatment. SGK overexpressing multiple myeloma cells were also relatively resistant to bortezomib in a murine xenograft model. Parental/control multiple myeloma cells demonstrated a rapid upregulation of SGK expression and activity (phosphorylation of NDRG-1) during exposure to bortezomib and an SGK inhibitor significantly enhanced bortezomib-induced apoptosis in cell lines and primary multiple myeloma cells. In addition, a multiple myeloma cell line selected for bortezomib resistance demonstrated enhanced SGK expression and SGK activity. Mechanistically, SGK overexpression constrained an ER stress-induced JNK proapoptotic pathway and experiments with a SEK mutant supported the notion that SGK's protection against bortezomib was mediated via its phosphorylation of SEK (MAP2K4) which abated SEK/JNK signaling. These data support a role for SGK inhibitors in the clinical setting for myeloma patients receiving treatment with ER stress inducers like bortezomib.
Enhanced SGK expression and activity in multiple myeloma cells contributes to resistance to ER stress, including bortezomib challenge.
为了评估血清和糖皮质激素调节激酶（SGK）在多发性骨髓瘤中的作用，我们将野生型或磷酸模拟型SGK异位表达于多发性骨髓瘤细胞系中。这些细胞对内质网应激诱导剂衣霉素、毒胡萝卜素和硼替佐米具有特异性抗性。相比之下，对地塞米松、血清饥饿或mTORC抑制剂的敏感性没有改变。从公共数据库挖掘基因组数据表明，多发性骨髓瘤患者低基线SGK表达与随后硼替佐米治疗完全缓解能力增强、治疗后疾病进展时间延长和总生存期延长相关。在小鼠异种移植模型中，过表达SGK的多发性骨髓瘤细胞对硼替佐米也相对耐药。亲本/对照多发性骨髓瘤细胞在暴露于硼替佐米期间表现出SGK表达和活性（NDRG-1磷酸化）迅速上调，SGK抑制剂显著增强硼替佐米诱导的细胞系和原发性多发性骨髓瘤细胞凋亡。此外，一株对硼替佐米耐药的多发性骨髓瘤细胞系显示SGK表达和活性增强。机制上，SGK过表达抑制内质网应激诱导的JNK促凋亡途径，用SEK突变体进行的实验支持以下观点：SGK对硼替佐米的保护作用是通过其对SEK（MAP2K4）的磷酸化介导的，这减弱了SEK/JNK信号传导。这些数据支持SGK抑制剂在接受内质网应激诱导剂如硼替佐米治疗的骨髓瘤患者临床治疗中的作用。
多发性骨髓瘤细胞中SGK表达和活性增强导致对内质网应激包括硼替佐米挑战的抗性。
