Choi Young Joon, Lee Hye Won, Lee Yun Sun, Shim Da Mi, Seo Sung Wook
Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul, 135-710, Korea.
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 135-710, Seoul, Korea.
Tumour Biol. 2016 Apr;37(4):4351-8. doi: 10.1007/s13277-015-4062-2. Epub 2015 Oct 23.
RRP12 (ribosomal RNA processing 12 homolog), a nucleolar protein, plays important roles in cell cycle progression and the response to deoxyribonucleic acid (DNA) damage in yeast cells. However, its role has not been investigated in mammalian cells that possess p53, which has close functional association to nucleolus. We explored the role of RRP12 in nucleolar stress condition using an osteosarcoma cell line, U2OS. To induce DNA damage and nucleolar disruption, two cytotoxic drugs, doxorubicin and actinomycin D were used. Cytotoxic stress resulted nucleolar disruption induced cell cycle arrest and apoptosis in U2OS cells. However, RRP12 overexpression promoted resistance to cytotoxic stress. In contrast, RRP12 silencing enhanced susceptibility to cytotoxic stress. During drug treatment, p53 activity and cell death were suppressed by RRP12 overexpression but promoted by RRP12 silencing. This study demonstrated that RRP12 was crucial for cell survival during cytotoxic stress via the repression of p53 stability. Thus, targeting RRP12 may enhance chemotherapeutic effect in cancers.
RRP12（核糖体RNA加工12同源物）是一种核仁蛋白，在酵母细胞的细胞周期进程以及对脱氧核糖核酸（DNA）损伤的反应中发挥重要作用。然而，其在具有与核仁功能密切相关的p53的哺乳动物细胞中的作用尚未得到研究。我们使用骨肉瘤细胞系U2OS探究了RRP12在核仁应激条件下的作用。为了诱导DNA损伤和核仁破坏，使用了两种细胞毒性药物，阿霉素和放线菌素D。细胞毒性应激导致核仁破坏，诱导U2OS细胞的细胞周期停滞和凋亡。然而，RRP12过表达促进了对细胞毒性应激的抗性。相反，RRP12沉默增强了对细胞毒性应激的敏感性。在药物治疗期间，RRP12过表达抑制了p53活性和细胞死亡，但RRP12沉默则促进了p53活性和细胞死亡。这项研究表明，RRP12通过抑制p53稳定性在细胞毒性应激期间对细胞存活至关重要。因此，靶向RRP12可能会增强癌症的化疗效果。
