Department of Biological Sciences; Notre Dame Integrated Imaging Facility, and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Cancer Res. 2013 Jun 15;73(12):3704-15. doi: 10.1158/0008-5472.CAN-12-2482.
Metastasis by cancer cells relies upon the acquisition of the ability to evade anoikis, a cell death process elicited by detachment from extracellular matrix (ECM). The molecular mechanisms that ECM-detached cancer cells use to survive are not understood. Striking increases in reactive oxygen species (ROS) occur in ECM-detached mammary epithelial cells, threatening cell viability by inhibiting ATP production, suggesting that ROS must be neutralized if cells are to survive ECM-detachment. Here, we report the discovery of a prominent role for antioxidant enzymes, including catalase and superoxide dismutase, in facilitating the survival of breast cancer cells after ECM-detachment. Enhanced expression of antioxidant enzymes in nonmalignant mammary epithelial cells detached from ECM resulted in ATP elevation and survival in the luminal space of mammary acini. Conversely, silencing antioxidant enzyme expression in multiple breast cancer cell lines caused ATP reduction and compromised anchorage-independent growth. Notably, antioxidant enzyme-deficient cancer cells were compromised in their ability to form tumors in mice. In aggregate, our results reveal a vital role for antioxidant enzyme activity in maintaining metabolic activity and anchorage-independent growth in breast cancer cells. Furthermore, these findings imply that eliminating antioxidant enzyme activity may be an effective strategy to enhance susceptibility to cell death in cancer cells that may otherwise survive ECM-detachment.
癌细胞的转移依赖于获得逃避失巢凋亡（anoikis）的能力，这是一种由细胞从细胞外基质（ECM）上脱离而引发的细胞死亡过程。ECM 脱离的癌细胞用来存活的分子机制尚不清楚。在 ECM 脱离的乳腺上皮细胞中，活性氧（ROS）显著增加，通过抑制 ATP 产生来威胁细胞活力，这表明如果细胞要在 ECM 脱离后存活，ROS 必须被中和。在这里，我们报告了抗氧化酶（包括过氧化氢酶和超氧化物歧化酶）在促进乳腺癌细胞在 ECM 脱离后的存活中发挥重要作用的发现。非恶性乳腺上皮细胞从 ECM 上脱离后，抗氧化酶的表达增强，导致 ATP 升高，并在乳腺腺泡的腔室内存活。相反，在多种乳腺癌细胞系中沉默抗氧化酶的表达会导致 ATP 减少，并损害非锚定依赖性生长。值得注意的是，抗氧化酶缺乏的癌细胞在形成肿瘤的能力上受到了损害。总的来说，我们的结果揭示了抗氧化酶活性在维持乳腺癌细胞代谢活性和非锚定依赖性生长中的重要作用。此外，这些发现表明，消除抗氧化酶活性可能是增强对 ECM 脱离后可能存活的癌细胞死亡敏感性的有效策略。
