Lin Yinzhi, Sidthipong Kulrawee, Ma Jun, Koide Naoki, Umezawa Kazuo, Kubota Tetsuo
Department of Molecular Target Medicine, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
Department of Microbiology and Immunology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
Exp Ther Med. 2021 Oct;22(4):1092. doi: 10.3892/etm.2021.10526. Epub 2021 Aug 2.
Plasmacytoma is one of the most difficult types of leukemia to treat, and it often invades the bone down to the marrow resulting in the development of multiple myeloma. NF-κB is often constitutively activated, and promotes metastasis and drug resistance in neoplastic cells. The present study assessed the cellular anticancer activity of an NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on mouse plasmacytoma SP2/0 cells. Cellular invasion was measured by Matrigel chamber assay, and apoptosis was assessed by detecting caspase-3 cleavage and by flow cytometric analysis with Annexin V. DHMEQ inhibited constitutively activated NF-κB at nontoxic concentrations. DHMEQ was also shown to inhibit cellular invasion of SP2/0 cells, as well as human myeloma KMS-11 and RPMI-8226 cells. The metastasis PCR array indicated that DHMEQ induced a decrease in KISS1 receptor (KISS1R) expression in SP2/0 cells. Knockdown of KISS1R by small interfering RNA suppressed cellular invasion, suggesting that KISS1R may serve an essential role in the invasion of SP2/0 cells. Furthermore, DHMEQ enhanced cytotoxicity of the anticancer agent melphalan in SP2/0 cells. Notably, DHMEQ inhibited the expression of NF-κB-dependent anti-apoptotic proteins, such as Bcl-XL, FLIP, and Bfl-1. In conclusion, inhibition of constitutively activated NF-κB by DHMEQ may be useful for future anti-metastatic and anticancer strategies for the treatment of plasmacytoma.
浆细胞瘤是最难治疗的白血病类型之一，它常常侵袭骨骼直至骨髓，导致多发性骨髓瘤的发生。核因子κB（NF-κB）常常持续激活，并促进肿瘤细胞的转移和耐药性。本研究评估了一种NF-κB抑制剂——去氢甲基环氧喹霉素（DHMEQ）对小鼠浆细胞瘤SP2/0细胞的细胞抗癌活性。通过基质胶小室试验检测细胞侵袭能力，通过检测半胱天冬酶-3的裂解情况以及用膜联蛋白V进行流式细胞术分析来评估细胞凋亡。DHMEQ在无毒浓度下抑制持续激活的NF-κB。DHMEQ还被证明能抑制SP2/0细胞以及人骨髓瘤KMS-11和RPMI-8226细胞的细胞侵袭。转移PCR阵列表明，DHMEQ诱导SP2/0细胞中亲吻素1受体（KISS1R）表达降低。用小干扰RNA敲低KISS1R可抑制细胞侵袭，这表明KISS1R可能在SP2/0细胞的侵袭中起关键作用。此外，DHMEQ增强了抗癌药物美法仑对SP2/0细胞的细胞毒性。值得注意的是，DHMEQ抑制了NF-κB依赖性抗凋亡蛋白如Bcl-XL、FLIP和Bfl-1的表达。总之，DHMEQ抑制持续激活的NF-κB可能对未来治疗浆细胞瘤的抗转移和抗癌策略有用。
