Tumor heterogeneity can be traced back to a small subset of cancer stem cells (CSCs), which can be derived from a single stem cell and show chemoresistance. Recent studies showed that CSCs are sensitive to mitochondrial targeting antibiotics such as doxycycline. However, little is known about how cancer cells undergo sphere formation and how antibiotics inhibit CSC proliferation. Here we show that under sphere-forming assay conditions, prostate cancer cells acquired CSC-like properties: promoted mitochondrial respiratory chain activity, expression of characteristic CSC markers and resistance to anticancer agents. Furthermore, those CSC-like properties could reversibly change depending on the culture conditions, suggesting some kinds of CSCs have plasticity in tumor microenvironments. The sphere-forming cells (i.e. cancer stem-like cells) showed increased contact between mitochondria and mitochondrial associated-endoplasmic reticulum (ER) membranes (MAM). Mitochondrial targeting doxycycline induced activating transcription factor 4 (ATF4) mediated expression of ER stress response and led to p53-upregulated modulator of apoptosis (PUMA)-dependent apoptosis only in the cancer stem-like cells. We also found that doxycycline effectively suppressed the sphere formation in vitro and blocked CD44v9-expressing tumor growth in vivo. In summary, these data provide new molecular findings that monolayer cancer cells acquire CSC-like properties in a reversible manner. These findings provide important insights into CSC biology and a potential new treatment of targeting mitochondria dependency.

中文翻译：

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强力霉素通过内质网应激选择性诱导具有癌干细胞样特性的细胞凋亡：干细胞可塑性的重要性。

肿瘤异质性可以追溯到癌症干细胞（CSC）的一小部分，其可以源自单个干细胞并显示化学抗性。最近的研究表明，CSC对线粒体靶向的抗生素（如强力霉素）敏感。但是，关于癌细胞如何进行球体形成以及抗生素如何抑制CSC增殖知之甚少。在这里，我们显示在形成球的测定条件下，前列腺癌细胞获得了CSC样的特性：促进了线粒体呼吸链活性，特征性CSC标记物的表达和对抗癌药的抗性。此外，这些CSC样特性可能会根据培养条件而可逆地变化，这表明某些CSC在肿瘤微环境中具有可塑性。球形细胞（即 癌干样细胞）显示线粒体和线粒体相关内质网（ERM）膜（MAM）之间的接触增加。线粒体靶向多西环素诱导ER应激反应的激活转录因子4（ATF4）介导的表达，并仅在癌干样细胞中导致凋亡的p53上调调节剂（PUMA）依赖性凋亡。我们还发现强力霉素在体外可有效抑制球的形成，并在体内阻断表达CD44v9的肿瘤的生长。总之，这些数据提供了新的分子发现，即单层癌细胞以可逆方式获得了CSC样特性。这些发现为CSC生物学以及靶向线粒体依赖性的潜在新疗法提供了重要的见解。