Dahlmann Mathias, Werner Rebecca, Kortüm Benedikt, Kobelt Dennis, Walther Wolfgang, Stein Ulrike
Experimental and Clinical Research Center, Charité University Medicine and the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
German Cancer Consortium (DKTK), Heidelberg, Germany.
Front Oncol. 2020 Apr 23;10:599. doi: 10.3389/fonc.2020.00599. eCollection 2020.
Treatment failure of solid cancers, represented by the development of drug resistance in the primary tumor or later outgrowth of drug resistant metastases, is the major cause of death for cancer patients. It represents an urgent clinical need for predictive biomarkers which indicate the success or failure of standard treatment regimens. Besides treatment prediction, interfering with cellular processes associated with drug resistance might improve treatment response by applying combination therapies. Metastasis-associated in colon cancer (MACC) 1 was identified in our group as a prognostic biomarker in human colorectal cancer, and has been established as key player, prognostic, and predictive biomarker for tumor progression and metastasis in a variety of solid cancers. Besides increased cell proliferation and motility, subsequently contributing to growth and metastatic spread of the primary tumor, MACC1 has also been shown to dysregulate apoptosis and is contributing to treatment resistance. Here we report the MACC1 dependent treatment resistance of colorectal cancer (CRC) cells to standard therapeutics like doxorubicin by upregulating ATP-binding cassette subfamily B member 1 (ABCB1) protein. Overexpression of MACC1 in CRC cells increased both its presence on the ABCB1 promoter and its transcriptional activity, resulting in elevated ABCB1 expression and thus treatment resistance to standard therapeutics. In contrast, depleting MACC1 increased intracellular drug concentrations, leading to better treatment response. We already identified the first MACC1 transcriptional inhibitors, such as lovastatin, by high-throughput screening of clinically approved small molecule drugs. These compounds inhibited cell motility but also restricted metastasis development in xenograft mouse models by reducing MACC1 expression. Here we report, that treating high MACC1 expressing CRC cells with a combination of statins and standard therapeutics increased the rate of cytotoxicity and resulted in higher treatment response.
实体癌的治疗失败，表现为原发性肿瘤中耐药性的产生或耐药性转移灶的后期出现，是癌症患者死亡的主要原因。这代表了对预测生物标志物的迫切临床需求，这些标志物可指示标准治疗方案的成败。除了治疗预测外，通过联合治疗干扰与耐药性相关的细胞过程可能会改善治疗反应。我们团队在人类结直肠癌中鉴定出结肠癌转移相关蛋白1（MACC1）作为一种预后生物标志物，并且它已被确立为多种实体癌中肿瘤进展和转移的关键因素、预后和预测生物标志物。除了增加细胞增殖和运动性，进而促进原发性肿瘤的生长和转移扩散外，MACC1还被证明会失调细胞凋亡并导致治疗耐药性。在此我们报告，结直肠癌细胞（CRC）对阿霉素等标准治疗药物的MACC1依赖性治疗耐药性是通过上调ATP结合盒亚家族B成员1（ABCB1）蛋白实现的。CRC细胞中MACC1的过表达增加了其在ABCB1启动子上的存在及其转录活性，导致ABCB1表达升高，从而对标准治疗药物产生耐药性。相反，敲低MACC1会增加细胞内药物浓度，从而产生更好的治疗反应。我们已经通过对临床批准的小分子药物进行高通量筛选，鉴定出首批MACC1转录抑制剂，如洛伐他汀。这些化合物抑制细胞运动性，还通过降低MACC1表达限制了异种移植小鼠模型中的转移发展。在此我们报告，用他汀类药物和标准治疗药物联合治疗高表达MACC1的CRC细胞会增加细胞毒性率，并产生更高的治疗反应。
