Hiraki Masayuki, Suzuki Yozo, Alam Maroof, Hinohara Kunihiko, Hasegawa Masanori, Jin Caining, Kharbanda Surender, Kufe Donald
Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
Sci Rep. 2016 May 24;6:26643. doi: 10.1038/srep26643.
Aberrant expression of myeloid cell leukemia-1 (MCL-1) is a major cause of drug resistance in triple-negative breast cancer (TNBC) cells. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly overexpressed in most TNBC. The present studies show that targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in TNBC cells with silencing or pharmacologic inhibition with GO-203 is associated with downregulation of MCL-1 levels. Targeting MUC1-C suppresses the MEK → ERK and PI3K → AKT pathways, and in turn destabilizes MCL-1. The small molecules ABT-737 and ABT-263 target BCL-2, BCL-XL and BCL-w, but not MCL-1. We show that treatment with ABT-737 increases reactive oxygen species and thereby MUC1-C expression. In this way, MUC1-C is upregulated in TNBC cells resistant to ABT-737 or ABT-263. We also demonstrate that MUC1-C is necessary for the resistance-associated increases in MCL-1 levels. Significantly, combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and drug resistant TNBC cells. These findings indicate that targeting MUC1-C is a potential strategy for reversing MCL-1-mediated resistance in TNBC.
髓系细胞白血病-1（MCL-1）的异常表达是三阴性乳腺癌（TNBC）细胞耐药的主要原因。黏蛋白1（MUC1）是一种异二聚体癌蛋白，在大多数TNBC中异常过表达。目前的研究表明，在TNBC细胞中通过沉默或用GO-203进行药理抑制来靶向致癌性MUC1 C末端亚基（MUC1-C）与MCL-1水平的下调有关。靶向MUC1-C可抑制MEK→ERK和PI3K→AKT信号通路，进而使MCL-1不稳定。小分子ABT-737和ABT-263靶向BCL-2、BCL-XL和BCL-w，但不靶向MCL-1。我们发现用ABT-737处理会增加活性氧，从而导致MUC1-C表达增加。通过这种方式，MUC1-C在对ABT-737或ABT-263耐药的TNBC细胞中上调。我们还证明MUC1-C是MCL-1水平与耐药相关增加所必需的。重要的是，将GO-203与ABT-737联合使用在抑制亲本和耐药TNBC细胞的存活方面具有协同作用。这些发现表明，靶向MUC1-C是逆转TNBC中MCL-1介导的耐药性的潜在策略。
