PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation.
PHB2 promotes colorectal cancer cell proliferation and tumorigenesis through NDUFS1-mediated oxidative phosphorylation.
复制标题
DOI：
10.1038/s41419-023-05575-9
复制
发表时间：
2023-01-20
影响因子：
9
通讯作者：
Ye, Yan
中科院分区：
文献类型：
--
作者：
Ren, Lin;Meng, Li;Gao, Jing;Lu, Mingdian;Guo, Chengyu;Li, Yunyun;Rong, Ziye;Ye, Yan
细胞能量代谢的改变是结直肠癌（CRC）的标志。越来越多的证据表明，氧化磷酸化（OXPHOS）上调，以满足肿瘤发生和发展的能量需求。然而，OXPHOS及其调控机制在CRC肿瘤发生和发展中的作用仍不清楚。在这里，我们发现，抑制素2（PHB2）的表达升高，在癌前腺瘤和CRC，促进细胞增殖和肿瘤的CRC。此外，PHB2的敲低显著降低CRC细胞中的线粒体OXPHOS水平。同时，通过免疫共沉淀和质谱法筛选并鉴定了作为PHB2结合伴侣的NADH：泛醌氧化还原酶核心亚基S1（NDUFS 1）。此外，PHB2直接与NDUFS 1相互作用，并且它们共定位于线粒体中，这促进NDUFS 1与NADH：泛醌氧化还原酶核心亚基V1（NDUFV 1）结合，调节复合物I的活性。因此，复合物I活性的部分抑制也消除了正常人肠上皮细胞和CRC细胞中由PHB2过表达诱导的细胞增殖增加。总的来说，这些结果表明，增加的PHB2直接与NDUFS 1相互作用，以稳定线粒体复合物I并增强其活性，导致OXPHOS水平上调，从而促进细胞增殖和CRC的肿瘤发生。我们的发现为理解CRC能量代谢提供了新的视角，也为CRC治疗提供了新的干预策略。
The alteration of cellular energy metabolism is a hallmark of colorectal cancer (CRC). Accumulating evidence has suggested oxidative phosphorylation (OXPHOS) is upregulated to meet the demand for energy in tumor initiation and development. However, the role of OXPHOS and its regulatory mechanism in CRC tumorigenesis and progression remain unclear. Here, we reveal that Prohibitin 2 (PHB2) expression is elevated in precancerous adenomas and CRC, which promotes cell proliferation and tumorigenesis of CRC. Additionally, knockdown of PHB2 significantly reduces mitochondrial OXPHOS levels in CRC cells. Meanwhile, NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), as a PHB2 binding partner, is screened and identified by co-immunoprecipitation and mass spectrometry. Furthermore, PHB2 directly interacts with NDUFS1 and they co-localize in mitochondria, which facilitates NDUFS1 binding to NADH:ubiquinone oxidoreductase core subunit V1 (NDUFV1), regulating the activity of complex I. Consistently, partial inhibition of complex I activity also abrogates the increased cell proliferation induced by overexpression of PHB2 in normal human intestinal epithelial cells and CRC cells. Collectively, these results indicate that increased PHB2 directly interacts with NDUFS1 to stabilize mitochondrial complex I and enhance its activity, leading to upregulated OXPHOS levels, thereby promoting cell proliferation and tumorigenesis of CRC. Our findings provide a new perspective for understanding CRC energy metabolism, as well as novel intervention strategies for CRC therapeutics.
登录
查看更多内容
DOI：
10.1016/j.bbcan.2018.06.001
发表时间：
2018-08
期刊：
Biochimica et biophysica acta. Reviews on cancer
影响因子：
--
作者：
Labuschagne CF;Zani F;Vousden KH
通讯作者：
Vousden KH
影响因子：
9.7
作者：
Huang, Qi;Chen, Zhigang;Huang, Jian
通讯作者：
Huang, Jian
影响因子：
14.5
作者：
Chen, Kuo;Lu, Pengwei;Aliev, Gjumrakch
通讯作者：
Aliev, Gjumrakch
影响因子：
4.6
作者：
Cheng, Jun;Gao, Feng;Zhou, Lin
通讯作者：
Zhou, Lin
DOI：
10.1186/s13046-022-02465-4
发表时间：
2022-09-02
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
通讯作者：
--