Muralikrishnan Vaishnavi, Fang Fang, Given Tyler C, Podicheti Ram, Chtcherbinine Mikhail, Metcalfe Tara X, Sriramkumar Shruthi, O'Hagan Heather M, Hurley Thomas D, Nephew Kenneth P
Cell, Molecular and Cancer Biology Graduate Program, Medical Sciences Department, Indiana University School of Medicine, Bloomington, IN 47405, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cancers (Basel). 2022 Jul 15;14(14):3437. doi: 10.3390/cancers14143437.
Ovarian cancer is a deadly disease attributed to late-stage detection as well as recurrence and the development of chemoresistance. Ovarian cancer stem cells (OCSCs) are hypothesized to be largely responsible for the emergence of chemoresistant tumors. Although chemotherapy may initially succeed at decreasing the size and number of tumors, it leaves behind residual malignant OCSCs. In this study, we demonstrate that aldehyde dehydrogenase 1A1 (ALDH1A1) is essential for the survival of OCSCs. We identified a first-in-class ALDH1A1 inhibitor, compound , and used as a tool to decipher the mechanism of stemness regulation by ALDH1A1. The treatment of OCSCs with significantly inhibited ALDH activity, the expression of stemness genes, and spheroid and colony formation. An in vivo limiting dilution assay demonstrated that significantly inhibited CSC frequency. A transcriptomic sequencing of cells treated with revealed a significant downregulation of genes related to stemness and chemoresistance as well as senescence and the senescence-associated secretory phenotype (SASP). We confirmed that inhibited the senescence and stemness induced by platinum-based chemotherapy in functional assays. Overall, these data establish that ALDH1A1 is essential for OCSC survival and that ALDH1A1 inhibition suppresses chemotherapy-induced senescence and stemness. Targeting ALDH1A1 using small-molecule inhibitors in combination with chemotherapy therefore presents a promising strategy to prevent ovarian cancer recurrence and has the potential for clinical translation.
卵巢癌是一种致命疾病，归因于晚期检测以及复发和化疗耐药性的发展。卵巢癌干细胞（OCSCs）被认为在很大程度上是化疗耐药肿瘤出现的原因。尽管化疗最初可能成功减小肿瘤的大小和数量，但它会留下残留的恶性OCSCs。在本研究中，我们证明醛脱氢酶1A1（ALDH1A1）对OCSCs的存活至关重要。我们鉴定出一种一流的ALDH1A1抑制剂化合物，并将其用作工具来破译ALDH1A1对干性调节的机制。用该化合物处理OCSCs显著抑制了ALDH活性、干性基因的表达以及球体和集落形成。体内极限稀释试验表明该化合物显著抑制了癌症干细胞频率。对用该化合物处理的细胞进行转录组测序显示，与干性、化疗耐药性以及衰老和衰老相关分泌表型（SASP）相关的基因显著下调。我们在功能试验中证实该化合物抑制了铂类化疗诱导的衰老和干性。总体而言，这些数据表明ALDH1A1对OCSCs存活至关重要，并且抑制ALDH1A1可抑制化疗诱导的衰老和干性。因此，使用小分子抑制剂靶向ALDH1A1并联合化疗是一种预防卵巢癌复发的有前景的策略，并且具有临床转化的潜力。
