线粒体启动减少决定了结肠癌干细胞的化疗耐药性。
Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells.
作者信息
Colak S, Zimberlin C D, Fessler E, Hogdal L, Prasetyanti P R, Grandela C M, Letai A, Medema J P
机构信息
LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, USA.
出版信息
Cell Death Differ. 2014 Jul;21(7):1170-7. doi: 10.1038/cdd.2014.37. Epub 2014 Mar 28.
Tumor heterogeneity is in part determined by the existence of cancer stem cells (CSCs) and more differentiated tumor cells. CSCs are considered to be the tumorigenic root of cancers and suggested to be chemotherapy resistant. Here we exploited an assay that allowed us to measure chemotherapy-induced cell death in CSCs and differentiated tumor cells simultaneously. This confirmed that CSCs are selectively resistant to conventional chemotherapy, which we revealed is determined by decreased mitochondrial priming. In agreement, lowering the anti-apoptotic threshold using ABT-737 and WEHI-539 was sufficient to enhance chemotherapy efficacy, whereas ABT-199 failed to sensitize CSCs. Our data therefore point to a crucial role of BCLXL in protecting CSCs from chemotherapy and suggest that BH3 mimetics, in combination with chemotherapy, can be an efficient way to target chemotherapy-resistant CSCs.
肿瘤异质性部分由癌症干细胞（CSCs）和分化程度更高的肿瘤细胞的存在所决定。癌症干细胞被认为是癌症的致瘤根源，并被认为具有化疗抗性。在这里，我们开发了一种检测方法，使我们能够同时测量化疗诱导的癌症干细胞和分化肿瘤细胞的细胞死亡。这证实了癌症干细胞对传统化疗具有选择性抗性，我们发现这是由线粒体启动减少所决定的。一致的是，使用ABT - 737和WEHI - 539降低抗凋亡阈值足以提高化疗疗效，而ABT - 199未能使癌症干细胞敏感化。因此，我们的数据表明BCLXL在保护癌症干细胞免受化疗方面起着关键作用，并表明BH3模拟物与化疗联合使用可能是靶向化疗抗性癌症干细胞的有效方法。
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