SIRT1 抑制线粒体过度融合相关的线粒体球形成，从而使口腔癌细胞在 mtROS 依赖性信号通路中的凋亡变得敏感。
SIRT1 inhibits mitochondrial hyperfusion associated mito-bulb formation to sensitize oral cancer cells for apoptosis in a mtROS-dependent signalling pathway.
发表日期：2023 Nov 10
作者：
Srimanta Patra, Amruta Singh, Prakash P Praharaj, Nitish K Mohanta, Mrutyunjay Jena, Birija S Patro, Ali Abusharha, Shankargouda Patil, Sujit K Bhutia
来源：
Cell Death & Disease
摘要：
SIRT1（NAD 依赖性蛋白脱乙酰酶 Sirtuin-1）是一种 III 类组蛋白脱乙酰酶，作为肿瘤抑制基因，在口腔癌细胞中表达下调。非凋亡剂量的顺铂 (CDDP) 下调 SIRT1 表达，提示耐药机制。 SIRT1 下调协调对 DNM1L 介导的线粒体裂变的抑制，随后导致过度融合的线粒体网络的形成。过度融合的线粒体网络通过稳定线粒体内膜嵴（形成模仿线粒体球状结构的线粒体核簇）并减少线粒体超氧化物的产生来抑制细胞凋亡，从而保留细胞色素 C (CYCS) 的释放。 SIRT1 的过度表达通过启动 DNM1L 调节的线粒体裂变来逆转线粒体过度融合。在过表达的细胞中，抑制线粒体过度融合和类核簇（mito-bulbs）可促进 CYCS 的细胞质释放，同时增强线粒体超氧化物的生成，从而随后诱导细胞凋亡。此外，用没食子酸（GA）（一种生物活性 SIRT1 激活剂）进行低剂量引发，可通过抑制线粒体过度融合来消除 CDDP 介导的细胞凋亡抑制。在这种情况下，SIRT1 敲低会阻碍 GA 引发的口腔癌细胞的凋亡激活。同样，SIRT1 在 CDDP 耐药性口腔癌来源的多倍体巨型癌细胞 (PGCC) 中过度表达，使细胞对细胞凋亡重新敏感。有趣的是，与 CDDP 协同治疗，GA 通过抑制线粒体过度融合来诱导 PGCC 凋亡。© 2023。作者。
SIRT1 (NAD-dependent protein deacetylase sirtuin-1), a class III histone deacetylase acting as a tumor suppressor gene, is downregulated in oral cancer cells. Non-apoptotic doses of cisplatin (CDDP) downregulate SIRT1 expression advocating the mechanism of drug resistance. SIRT1 downregulation orchestrates inhibition of DNM1L-mediated mitochondrial fission, subsequently leading to the formation of hyperfused mitochondrial networks. The hyperfused mitochondrial networks preserve the release of cytochrome C (CYCS) by stabilizing the mitochondrial inner membrane cristae (formation of mitochondrial nucleoid clustering mimicking mito-bulb like structures) and reducing the generation of mitochondrial superoxide to inhibit apoptosis. Overexpression of SIRT1 reverses the mitochondrial hyperfusion by initiating DNM1L-regulated mitochondrial fission. In the overexpressed cells, inhibition of mitochondrial hyperfusion and nucleoid clustering (mito-bulbs) facilitates the cytoplasmic release of CYCS along with an enhanced generation of mitochondrial superoxide for the subsequent induction of apoptosis. Further, low-dose priming with gallic acid (GA), a bio-active SIRT1 activator, nullifies CDDP-mediated apoptosis inhibition by suppressing mitochondrial hyperfusion. In this setting, SIRT1 knockdown hinders apoptosis activation in GA-primed oral cancer cells. Similarly, SIRT1 overexpression in the CDDP resistance oral cancer-derived polyploid giant cancer cells (PGCCs) re-sensitizes the cells to apoptosis. Interestingly, synergistically treated with CDDP, GA induces apoptosis in the PGCCs by inhibiting mitochondrial hyperfusion.© 2023. The Author(s).