Singh Shree Ram, Zeng Xiankun, Zhao Jiangsha, Liu Ying, Hou Gerald, Liu Hanhan, Hou Steven X
The Basic Research Laboratory, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
Nature. 2016 Oct 6;538(7623):109-113. doi: 10.1038/nature19788. Epub 2016 Sep 28.
Cancer stem cells (CSCs) may be responsible for tumour dormancy, relapse and the eventual death of most cancer patients. In addition, these cells are usually resistant to cytotoxic conditions. However, very little is known about the biology behind this resistance to therapeutics. Here we investigated stem-cell death in the digestive system of adult Drosophila melanogaster. We found that knockdown of the coat protein complex I (COPI)-Arf79F (also known as Arf1) complex selectively killed normal and transformed stem cells through necrosis, by attenuating the lipolysis pathway, but spared differentiated cells. The dying stem cells were engulfed by neighbouring differentiated cells through a draper-myoblast city-Rac1-basket (also known as JNK)-dependent autophagy pathway. Furthermore, Arf1 inhibitors reduced CSCs in human cancer cell lines. Thus, normal or cancer stem cells may rely primarily on lipid reserves for energy, in such a way that blocking lipolysis starves them to death. This finding may lead to new therapies that could help to eliminate CSCs in human cancers.
癌症干细胞（CSCs）可能是肿瘤休眠、复发以及大多数癌症患者最终死亡的原因。此外，这些细胞通常对细胞毒性条件具有抗性。然而，对于这种对治疗产生抗性背后的生物学机制，我们知之甚少。在此，我们研究了成年黑腹果蝇消化系统中的干细胞死亡情况。我们发现，通过减弱脂解途径，敲低衣被蛋白复合物I（COPI）-Arf79F（也称为Arf1）复合物会选择性地通过坏死杀死正常干细胞和转化干细胞，但对分化细胞没有影响。濒死的干细胞会通过一种依赖于draper-成肌细胞城市-Rac1-篮状蛋白（也称为JNK）的自噬途径被邻近的分化细胞吞噬。此外，Arf1抑制剂可减少人类癌细胞系中的癌症干细胞。因此，正常干细胞或癌症干细胞可能主要依赖脂质储备来获取能量，以至于阻断脂解作用会使它们饿死。这一发现可能会带来有助于消除人类癌症中癌症干细胞的新疗法。
