Saha Shilpi, Mukherjee Shravanti, Mazumdar Minakshi, Manna Argha, Khan Poulami, Adhikary Arghya, Kajal Kirti, Jana Debarshi, Sa Gaurisankar, Mukherjee Sanhita, Sarkar Diptendra K, Das Tanya
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
Department of Surgery, SSKM Hospital, Kolkata, West Bengal, India.
Transl Res. 2015 May;165(5):558-77. doi: 10.1016/j.trsl.2014.10.011. Epub 2014 Nov 1.
Chemotherapy resistance is a major clinical challenge for the management of locally advanced breast cancer. Accumulating evidence suggests a major role of cancer stem cells (CSCs) in chemoresistance evoking the requirement of drugs that selectively target CSCs in combination with chemotherapy. Here, we report that mithramycin A, a known specificity protein (Sp)1 inhibitor, sensitizes breast CSCs (bCSCs) by perturbing the expression of drug efflux transporters, ATP-binding cassette sub-family G, member 2 (ABCG2) and ATP-binding cassette sub-family C, member 1 (ABCC1), survival factors, B-cell lymphoma 2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and, stemness regulators, octamer-binding transcription factor 4 (Oct4) and Nanog, which are inherently upregulated in these cells compared with the rest of the tumor population. In-depth analysis revealed that aberrant overexpression of Sp1 in bCSCs transcriptionally upregulates (1) resistance-promoting genes to protect these cells from genotoxic therapy, and (2) stemness regulators to sustain self-renewal potential of these cells. However, mithramycin A causes transcriptional suppression of these chemoresistant and self-renewal genes by inhibiting Sp1 recruitment to their promoters. Under such antisurvival microenvironment, chemotherapeutic agent doxorubicin induces apoptosis in bCSCs via DNA damage-induced reactive oxygen species generation. Cumulatively, our findings raise the possibility that mithramycin A might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to eliminate CSCs. This will consequently lead to the improvement of therapeutic outcome for the treatment-resistant breast carcinomas.
化疗耐药是局部晚期乳腺癌治疗中的一项重大临床挑战。越来越多的证据表明，癌症干细胞（CSCs）在化疗耐药中起主要作用，这就需要有能选择性靶向CSCs的药物与化疗联合使用。在此，我们报告称，放线菌素A（一种已知的特异性蛋白（Sp）1抑制剂）通过干扰药物外排转运蛋白ATP结合盒亚家族G成员2（ABCG2）和ATP结合盒亚家族C成员1（ABCC1）、生存因子B细胞淋巴瘤2（Bcl-2）和X连锁凋亡抑制蛋白（XIAP）以及干性调节因子八聚体结合转录因子4（Oct4）和Nanog的表达，使乳腺CSCs（bCSCs）敏感化。与肿瘤群体的其他细胞相比，这些因子在这些细胞中原本就上调。深入分析表明，bCSCs中Sp1的异常过表达在转录水平上上调（1）促进耐药的基因以保护这些细胞免受基因毒性治疗，以及（2）干性调节因子以维持这些细胞的自我更新潜能。然而，放线菌素A通过抑制Sp1募集到其启动子上来导致这些化疗耐药和自我更新基因的转录抑制。在这种抗生存微环境下，化疗药物阿霉素通过DNA损伤诱导的活性氧生成诱导bCSCs凋亡。总的来说，我们的研究结果提出了一种可能性，即放线菌素A可能会成为与现有无法消除CSCs的化疗药物联合治疗中有前景的药物。这将因此改善难治性乳腺癌的治疗效果。
