Onul Abdullah, Elseth Kim M, De Vitto Humberto, Paradise William A, Vesper Benjamin J, Tarjan Gabor, Haines G Kenneth, Rumjanek Franklin D, Radosevich James A
Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, 801 S Paulina St, Chicago, IL 60612, USA.
Tumour Biol. 2012 Jun;33(3):739-48. doi: 10.1007/s13277-011-0271-5. Epub 2012 Mar 10.
Previously, we demonstrated that A549, a human lung cancer cell line, could be adapted to the free radical nitric oxide (NO●). NO● is known to be over expressed in human tumors. The original cell line, A549 (parent), and the newly adapted A549-HNO (which has a more aggressive phenotype) serve as a useful model system to study the biology of NO●. To see if tumor cells can similarly be adapted to any free radical with the same outcome, herein we successfully adapted A549 cells to high levels of hydrogen peroxide (HHP). A549-HHP, the resulting cell line, was more resistant and grew better then the parent cell line, and showed the following characteristics: (1) resistance to hydrogen peroxide, (2) resistance to NO●, (3) growth with and without hydrogen peroxide, and (4) resistance to doxorubicin. Gene chip analysis was used to determine the global gene expression changes between A549-parent and A549-HHP and revealed significant changes in the expression of over 1,700 genes. This gene profile was markedly different from that obtained from the A549-HNO cell line. The mitochondrial DNA content of the A549-HHP line determined by quantitative PCR favored a change for a more anaerobic metabolic profile. Our findings suggest that any free radical can induce resistance to other free radicals; this is especially important given that radiation therapy and many chemotherapeutic agents exert their effect via free radicals. Utilizing this model system to better understand the role of free radicals in tumor biology will help to develop new therapeutic approaches to treat lung cancer.
此前，我们证明了人肺癌细胞系A549能够适应自由基一氧化氮（NO●）。已知NO●在人类肿瘤中过度表达。原始细胞系A549（亲本）和新适应的A549 - HNO（具有更具侵袭性的表型）是研究NO●生物学的有用模型系统。为了探究肿瘤细胞是否能以同样的方式适应任何自由基并产生相同的结果，在此我们成功地使A549细胞适应了高水平的过氧化氢（HHP）。由此产生的细胞系A549 - HHP比亲本细胞系更具抗性且生长更好，并表现出以下特征：（1）对过氧化氢有抗性；（2）对NO●有抗性；（3）在有和没有过氧化氢的情况下都能生长；（4）对阿霉素有抗性。基因芯片分析用于确定A549亲本细胞系和A549 - HHP细胞系之间的整体基因表达变化，结果显示超过1700个基因的表达发生了显著变化。该基因图谱与从A549 - HNO细胞系获得的图谱明显不同。通过定量PCR测定的A549 - HHP细胞系的线粒体DNA含量有利于向更厌氧的代谢谱转变。我们的研究结果表明，任何自由基都能诱导对其他自由基产生抗性；鉴于放射治疗和许多化疗药物都是通过自由基发挥作用，这一点尤为重要。利用这个模型系统更好地理解自由基在肿瘤生物学中的作用，将有助于开发治疗肺癌的新方法。
