Vogel Rachel Isaksson, Coughlin Kathleen, Scotti Alessandra, Iizuka Yoshie, Anchoori Ravi, Roden Richard B S, Marastoni Mauro, Bazzaro Martina
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Obstetrics, Gynecology and Women's Heath, University of Minnesota, Minneapolis, Minnesota, USA.
Oncotarget. 2015 Feb 28;6(6):4159-70. doi: 10.18632/oncotarget.2904.
Breast cancer is one of the leading causes of cancer death among women in the United States. Patients expressing the estrogen and progesterone receptor (ER and PR) and human epidermal growth factor 2 (HER-2) tumor markers have favorable prognosis and efficacious therapeutic options. In contrast, tumors that are negative for these markers (triple-negative) have a disproportionate share of morbidity and mortality due to lack of a validated molecular target. Deubiquitinating enzymes (DUBs) are a critical component of ubiquitin-proteasome-system degradation and have been shown to be differentially expressed and activated in a number of cancers, including breast, with their aberrant activity linked to cancer prognosis and clinical outcome. We evaluated the effect of the DUB inhibitors b-AP15 and RA-9 alone and in combination with early- and late-stage lysosomal inhibitors on cell viability in a panel of triple negative breast cancer (TNBC) cell lines. Our results indicate small-molecule DUB inhibitors have a profound effect on TNBC viability and lead to activation of autophagy as a cellular mechanism to compensate for ubiquitin-proteasome-system stress. Treatment with sub-optimal doses of DUB and lysosome inhibitors synergistically kills TNBC cells. This supports the evaluation of DUB inhibition, in combination with lysosomal inhibition, as a therapeutic approach for the treatment of TNBC.
乳腺癌是美国女性癌症死亡的主要原因之一。表达雌激素和孕激素受体（ER和PR）以及人表皮生长因子2（HER-2）肿瘤标志物的患者预后良好且有有效的治疗选择。相比之下，这些标志物呈阴性的肿瘤（三阴性）由于缺乏经过验证的分子靶点，在发病率和死亡率中所占比例过高。去泛素化酶（DUBs）是泛素-蛋白酶体系统降解的关键组成部分，已被证明在包括乳腺癌在内的多种癌症中存在差异表达和激活，其异常活性与癌症预后和临床结果相关。我们评估了DUB抑制剂b-AP15和RA-9单独以及与早期和晚期溶酶体抑制剂联合使用对一组三阴性乳腺癌（TNBC）细胞系细胞活力的影响。我们的结果表明，小分子DUB抑制剂对TNBC活力有深远影响，并导致自噬激活，作为一种细胞机制来补偿泛素-蛋白酶体系统应激。用次优剂量的DUB和溶酶体抑制剂联合处理可协同杀死TNBC细胞。这支持将DUB抑制与溶酶体抑制联合作为治疗TNBC的一种治疗方法进行评估。
