Glinsky Gennadi V, Godugu Kavitha, Sudha Thangirala, Rajabi Mehdi, Chittur Sridar V, Hercbergs Aleck A, Mousa Shaker A, Davis Paul J
Institute of Engineering in Medicine, University of California San Diego, San Diego, CA 92037, USA.
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rensselaer, NY 12144, USA.
Metabolites. 2022 Apr 4;12(4):325. doi: 10.3390/metabo12040325.
Chemically modified forms of tetraiodothyroacetic acid (tetrac), an L-thyroxine derivative, have been shown to exert their anticancer activity at plasma membrane integrin αvβ3 of tumor cells. Via a specific hormone receptor on the integrin, tetrac-based therapeutic agents modulate expression of genes relevant to cancer cell proliferation, survival and energy metabolism. P-bi-TAT, a novel bivalent tetrac-containing synthetic compound has anticancer activity in vitro and in vivo against glioblastoma multiforme (GBM) and other types of human cancers. In the current study, microarray analysis was carried out on a primary culture of human GBM cells exposed to P-bi-TAT (10 tetrac equivalent) for 24 h. P-bi-TAT significantly affected expression of a large panel of genes implicated in cancer cell stemness, growth, survival and angiogenesis. Recent interest elsewhere in ATP synthase as a target in GBM cells caused us to focus attention on expression of genes involved in energy metabolism. Significantly downregulated transcripts included multiple energy-metabolism-related genes: electron transport chain genes ATP5A1 (ATP synthase 1), ATP51, ATP5G2, COX6B1 (cytochrome c oxidase subunit 6B1), NDUFA8 (NADH dehydrogenase (ubiquinone) FA8), NDUFV2I and other NDUF genes. The NDUF and ATP genes are also relevant to control of oxidative phosphorylation and transcription. Qualitatively similar actions of P-bi-TAT on expression of subsets of energy-metabolism-linked genes were also detected in established human GBM and pancreatic cancer cell lines. In conclusion, acting at αvβ3 integrin, P-bi-TAT caused downregulation in human cancer cells of expression of a large number of genes involved in electron transport and oxidative phosphorylation. These observations suggest that cell surface thyroid hormone receptors on αvβ3 regulate expression of genes relevant to tumor cell stemness and energy metabolism.
四碘甲状腺乙酸（tetrac）是一种L-甲状腺素衍生物，其化学修饰形式已被证明可在肿瘤细胞质膜整合素αvβ3上发挥抗癌活性。通过整合素上的特定激素受体，基于tetrac的治疗剂可调节与癌细胞增殖、存活和能量代谢相关的基因表达。P-bi-TAT是一种新型的含二价tetrac的合成化合物，在体外和体内对多形性胶质母细胞瘤（GBM）和其他类型的人类癌症具有抗癌活性。在本研究中，对暴露于P-bi-TAT（10个tetrac当量）24小时的人GBM细胞原代培养物进行了微阵列分析。P-bi-TAT显著影响了一大批与癌细胞干性、生长、存活和血管生成相关的基因表达。最近其他地方对ATP合酶作为GBM细胞靶点的关注使我们将注意力集中在参与能量代谢的基因表达上。显著下调的转录本包括多个与能量代谢相关的基因：电子传递链基因ATP5A1（ATP合酶1）、ATP51、ATP5G2、COX6B1（细胞色素c氧化酶亚基6B1）、NDUFA8（NADH脱氢酶（泛醌）FA8）、NDUFV2I和其他NDUF基因。NDUF和ATP基因也与氧化磷酸化和转录的控制有关。在已建立的人GBM和胰腺癌细胞系中也检测到P-bi-TAT对能量代谢相关基因子集表达的定性相似作用。总之，P-bi-TAT作用于αvβ3整合素，导致人类癌细胞中大量参与电子传递和氧化磷酸化的基因表达下调。这些观察结果表明，αvβ3上的细胞表面甲状腺激素受体调节与肿瘤细胞干性和能量代谢相关的基因表达。
