Ohya Yuki, Ogiso Yuri, Matsuda Masaya, Sakae Harumi, Nishida Kentaro, Miki Yasuhiro, Fox Todd E, Kester Mark, Sakamoto Wataru, Nabe Takeshi, Kitatani Kazuyuki
Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata 573-0101, Japan.
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Cells. 2024 Feb 26;13(5):405. doi: 10.3390/cells13050405.
Regulated necrosis, termed necroptosis, represents a potential therapeutic target for refractory cancer. Ceramide nanoliposomes (CNLs), considered potential chemotherapeutic agents, induce necroptosis by targeting the activating protein mixed lineage kinase domain-like protein (MLKL). In the present study, we examined the potential of pronecroptotic therapy using CNLs for refractory triple-negative breast cancer (TNBC), for which there is a lack of definite and effective therapeutic targets among the various immunohistological subtypes of breast cancer. MLKL mRNA expression in tumor tissues was significantly higher in TNBC patients than in those with non-TNBC subtypes. Similarly, among the 50 breast cancer cell lines examined, MLKL expression was higher in TNBC-classified cell lines. TNBC cell lines were more susceptible to the therapeutic effects of CNLs than the non-TNBC subtypes of breast cancer cell lines. In TNBC-classified MDA-MB-231 cells, the knockdown of MLKL suppressed cell death induced by CNLs or the active substance short-chain C-ceramide. Accordingly, TNBC cells were prone to CNL-evoked necroptotic cell death. These results will contribute to the development of CNL-based pronecroptotic therapy for TNBC.
程序性坏死，即坏死性凋亡，是难治性癌症的一个潜在治疗靶点。神经酰胺纳米脂质体（CNLs）被认为是潜在的化疗药物，通过靶向激活蛋白混合谱系激酶结构域样蛋白（MLKL）诱导坏死性凋亡。在本研究中，我们研究了使用CNLs进行促坏死性凋亡治疗难治性三阴性乳腺癌（TNBC）的潜力，在乳腺癌的各种免疫组织学亚型中，TNBC缺乏明确有效的治疗靶点。TNBC患者肿瘤组织中的MLKL mRNA表达显著高于非TNBC亚型患者。同样，在所检测的50种乳腺癌细胞系中，MLKL表达在TNBC分类的细胞系中更高。TNBC细胞系比乳腺癌细胞系的非TNBC亚型对CNLs的治疗效果更敏感。在TNBC分类的MDA-MB-231细胞中，MLKL的敲低抑制了CNLs或活性物质短链C-神经酰胺诱导的细胞死亡。因此，TNBC细胞易于发生CNL诱发的坏死性凋亡细胞死亡。这些结果将有助于开发基于CNL的TNBC促坏死性凋亡治疗方法。
