Cai Dongjing, Xu Xia, Zeng Weiqian, Wang Zheng, Chen Cheng, Mo Yunan, Meekrathok Piyanat, Wang Dandan, Peng Pengwei, Peng Zhigang, Qiu Jian
Hunan Key Laboratory of Molecular Precision Medicine, Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
Department of General Practice, Xiangya Hospital, Central South University, Changsha, 410008, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.
Free Radic Biol Med. 2024 Nov 1;224:382-392. doi: 10.1016/j.freeradbiomed.2024.08.027. Epub 2024 Aug 28.
Cellular senescence is a natural barrier of the transition from premalignant cells to invasive cancer. Pharmacological induction of senescence has been proposed as a possible anticancer strategy. In this study, we found that deoxyarbutin inhibited the growth of glioblastoma (GBM) cells by inducing cellular senescence, independent of tyrosinase expression. Instead, deoxyarbutin induced mitochondrial oxidative stress and damage. These aberrant mitochondria were key to the p53-dependent senescence of GBM cells. Facilitating autophagy or mitigating mitochondrial oxidative stress both suppressed p53 expression and alleviated cellular senescence induced by deoxyarbutin. Thus, our study reveals that deoxyarbutin induces mitochondrial oxidative stress to trigger the p53-dependent senescence of GBM cells. Importantly, deoxyarbutin treatment resulted in accumulation of p53, induction of cellular senescence, and inhibition of tumor growth in a subcutaneous tumor model of mouse. In conclusion, our study reveals that deoxyarbutin has therapeutic potential for GBM by inducing mitochondrial oxidative stress for p53-dependent senescence of GBM cells.
细胞衰老 是癌前细胞向侵袭性癌症转变的天然屏障。诱导衰老的药理学方法已被提出作为一种可能的抗癌策略。在本研究中，我们发现脱氧熊果苷通过诱导细胞衰老来抑制胶质母细胞瘤（GBM）细胞的生长，这与酪氨酸酶表达无关。相反，脱氧熊果苷诱导线粒体氧化应激和损伤。这些异常的线粒体是GBM细胞p53依赖性衰老的关键。促进自噬或减轻线粒体氧化应激均抑制p53表达并减轻脱氧熊果苷诱导的细胞衰老。因此，我们的研究表明，脱氧熊果苷诱导线粒体氧化应激以触发GBM细胞的p53依赖性衰老。重要的是，在小鼠皮下肿瘤模型中，脱氧熊果苷治疗导致p53积累、细胞衰老诱导和肿瘤生长抑制。总之，我们的研究表明，脱氧熊果苷通过诱导线粒体氧化应激促进GBM细胞的p53依赖性衰老，从而具有治疗GBM的潜力。
