Department of Mechanisms of Anticancer Therapy, R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, Kiev, Ukraine.
Int J Oncol. 2013 Nov;43(5):1481-6. doi: 10.3892/ijo.2013.2063. Epub 2013 Aug 20.
The development of resistance of cancer cells to therapeutic agents is the major obstacle in the successful treatment of breast cancer and the main cause of breast cancer recurrence. The results of several studies have demonstrated an important role of altered cellular iron metabolism in the progression of breast cancer and suggested that iron metabolism may be involved in the acquisition of a cancer cell drug-resistant phenotype. In the present study, we show that human MCF-7 breast cancer cells with an acquired resistance to the chemotherapeutic drugs doxorubicin (MCF-7/DOX) and cisplatin (MCF-7/CDDP) exhibited substantial alterations in the intracellular iron content and levels of iron-regulatory proteins involved in the cellular uptake, storage and export of iron, especially in profoundly increased levels of ferritin light chain (FTL) protein. The increased levels of FTL in breast cancer indicate that FTL may be used as a diagnostic and prognostic marker for breast cancer. Additionally, we demonstrate that targeted downregulation of FTL protein by the microRNA miR-133a increases sensitivity of MCF-7/DOX and MCF-7/CDDP cells to doxorubicin and cisplatin. These results suggest that correction of iron metabolism abnormalities may substantially improve the efficiency of breast cancer treatment.
癌细胞对治疗药物产生耐药性是乳腺癌成功治疗的主要障碍，也是乳腺癌复发的主要原因。几项研究的结果表明，细胞铁代谢的改变在乳腺癌的进展中起着重要作用，并提示铁代谢可能参与了癌细胞获得耐药表型。在本研究中，我们发现对化疗药物阿霉素（MCF-7/DOX）和顺铂（MCF-7/CDDP）具有获得性耐药的人 MCF-7 乳腺癌细胞，其细胞内铁含量和参与铁摄取、储存和输出的铁调节蛋白的水平发生了实质性改变，特别是铁蛋白轻链（FTL）蛋白的水平显著增加。乳腺癌中 FTL 的增加表明 FTL 可作为乳腺癌的诊断和预后标志物。此外，我们还证明，通过 microRNA miR-133a 靶向下调 FTL 蛋白可增加 MCF-7/DOX 和 MCF-7/CDDP 细胞对阿霉素和顺铂的敏感性。这些结果表明，纠正铁代谢异常可能会显著提高乳腺癌治疗的效率。
