Abdel-Samad Rana, Aouad Patrick, Gali-Muhtasib Hala, Sweidan Zeinab, Hmadi Raed, Kadara Humam, D'Andrea Egildo Luca, Fucci Alessandra, Pisano Claudio, Darwiche Nadine
Department of Biochemistry and Molecular Genetics, American University of BeirutBeirut, Lebanon.
Faculty of Health Sciences, University of BalamandBeirut, Lebanon.
Am J Cancer Res. 2018 Jan 1;8(1):39-55. eCollection 2018.
Despite advances in therapeutic strategies, colorectal cancer (CRC) remains the third cause of cancer-related deaths with a relatively low survival rate. Resistance to standard chemotherapy represents a major hurdle in disease management; therefore, developing new therapeutic agents demands a thorough understanding of their mechanisms of action. One of these compounds is ST1926, an adamantyl retinoid that has shown potent antitumor activities in several human cancer models. Here, we show that ST1926 selectively suppressed the proliferation of CRC cells while sparing normal counterparts, and significantly reduced tumor volume in a xenograft cancer mouse model. Next, we investigated the effects of ST1926 in CRC cells and observed early DNA damage, S-phase arrest, dissipation of mitochondrial membrane potential, and apoptosis induction, in a and -independent manner. To address the underlying mechanism of resistance to ST1926, we generated ST1926-resistant HCT116 cells and sequenced DNA polymerase α (), which was reported to be a direct target to the drug's parent molecule, CD437. We identified similar mutations in that conferred resistance to ST1926 and CD437. These mutations were absent in 5-fluorouracil-resistant HCT116 cells, clearly validating the specificity of these mutations to the lack of DNA damage and acquired resistance to ST1926. ST1926 also inhibited POLA1 activity and reduced its protein expression levels. Further, in silico analysis of normal and malignant tissue expression data demonstrated that levels are elevated in CRC cells and tissues compared to normal counterparts as well as to other cancer types. Our findings highlight previously uncharacterized mechanisms of action of ST1926 in CRC and suggest that elevated expression is a pertinent molecular feature and an attractive target in CRC.
尽管治疗策略取得了进展，但结直肠癌（CRC）仍是癌症相关死亡的第三大原因，生存率相对较低。对标准化疗的耐药性是疾病管理中的一个主要障碍；因此，开发新的治疗药物需要深入了解其作用机制。其中一种化合物是ST1926，一种金刚烷基类视黄醇，在几种人类癌症模型中显示出强大的抗肿瘤活性。在这里，我们表明ST1926选择性地抑制CRC细胞的增殖，同时不影响正常细胞，并在异种移植癌小鼠模型中显著减小肿瘤体积。接下来，我们研究了ST1926对CRC细胞的影响，观察到早期DNA损伤、S期阻滞、线粒体膜电位消散和凋亡诱导，且与p53无关。为了探究对ST1926耐药的潜在机制，我们构建了对ST1926耐药的HCT116细胞，并对DNA聚合酶α（POLA1）进行测序，据报道它是该药物母体分子CD437的直接靶点。我们在POLA1中鉴定出了赋予对ST1926和CD437耐药性的相似突变。这些突变在对5-氟尿嘧啶耐药的HCT11细胞中不存在，这清楚地证实了这些突变对缺乏DNA损伤和获得性ST1926耐药性的特异性。ST1926还抑制POLA1活性并降低其蛋白表达水平。此外，对正常和恶性组织表达数据的计算机分析表明，与正常组织以及其他癌症类型相比，CRC细胞和组织中的POLA1水平升高。我们的研究结果突出了ST1926在CRC中以前未被描述的作用机制，并表明POLA1表达升高是CRC中一个相关的分子特征和有吸引力的靶点。
