Lin Hung-Yun, Chin Yu-Tang, Nana André Wendindondé, Shih Ya-Jung, Lai Hsuan-Yu, Tang Heng-Yuan, Leinung Matthew, Mousa Shaker A, Davis Paul J
PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan.
Steroids. 2016 Oct;114:59-67. doi: 10.1016/j.steroids.2016.05.006. Epub 2016 May 21.
The PD-1 (programmed death-1)/PD-L1 (PD-ligand 1) checkpoint is a critical regulator of activated T cell-cancer cell interactions, defending tumor cells against immune destruction. Nano-diamino-tetrac (NDAT; Nanotetrac) is an anticancer/anti-angiogenic agent targeted to the thyroid hormone-tetrac receptor on the extracellular domain of integrin αvβ3. NDAT inhibits the cancer cell PI3-K and MAPK signal transduction pathways that are critical to PD-L1 gene expression. We examined actions in vitro of thyroid hormone (l-thyroxine, T) and NDAT on PD-L1 mRNA abundance (qPCR) and PD-L1 protein content in human breast cancer (MDA-MB-231) cells and colon carcinoma (HCT116 and HT-29) cells. In MDA-MB-231 cells, a physiological concentration of T (10M total; 10M free hormone) stimulated PD-L1 gene expression by 38% and increased PD-L1 protein by 2.7-fold (p<0.05, all changes). NDAT (10M) reduced PD-L1 in T-exposed cells by 21% (mRNA) and 39% (protein) (p<0.05, all changes). In HCT116 cells, T enhanced PD-L1 gene expression by 17% and protein content by 24% (p<0.05). NDAT reduced basal PD-L1 mRNA by 35% and protein by 31% and in T-treated cells lowered mRNA by 33% and protein by 66%. In HT-29 cells, T increased PD-L1 mRNA by 62% and protein by 27%. NDAT lowered basal and T-stimulated responses in PD-L1 mRNA and protein by 35-40% (p<0.05). Activation of ERK1/2 was involved in T-induced PD-L1 accumulation. We propose that, by a nongenomic mechanism, endogenous T may clinically support activity of the defensive PD-1/PD-L1 checkpoint in tumor cells. NDAT non-immunologically suppresses basal and T-induced PD-L1 gene expression and protein accumulation in cancer cells.
程序性死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）免疫检查点是活化T细胞与癌细胞相互作用的关键调节因子，可保护肿瘤细胞免受免疫破坏。纳米二氨基四酸（NDAT；纳米四酸）是一种靶向整合素αvβ3细胞外结构域上甲状腺激素-四酸受体的抗癌/抗血管生成剂。NDAT抑制对PD-L1基因表达至关重要的癌细胞PI3-K和MAPK信号转导通路。我们研究了甲状腺激素（L-甲状腺素，T）和NDAT在体外对人乳腺癌（MDA-MB-231）细胞和结肠癌细胞（HCT116和HT-29）中PD-L1 mRNA丰度（qPCR）和PD-L1蛋白含量的影响。在MDA-MB-231细胞中，生理浓度的T（总浓度10μM；游离激素10μM）刺激PD-L1基因表达增加38%，PD-L1蛋白增加2.7倍（所有变化p<0.05）。NDAT（10μM）使暴露于T的细胞中PD-L1的mRNA减少21%，蛋白减少39%（所有变化p<0.05）。在HCT116细胞中，T使PD-L1基因表达增加17%，蛋白含量增加24%（p<0.05）。NDAT使基础PD-L1 mRNA减少35%，蛋白减少31%，在T处理的细胞中使mRNA减少33%，蛋白减少66%。在HT-29细胞中，T使PD-L1 mRNA增加62%，蛋白增加27%。NDAT使基础和T刺激的PD-L1 mRNA和蛋白反应降低35-40%（p<0.05）。ERK1/2的激活参与了T诱导的PD-L1积累。我们提出，内源性T可能通过一种非基因组机制在临床上支持肿瘤细胞中防御性PD-1/PD-L1免疫检查点的活性。NDAT通过非免疫方式抑制癌细胞中基础和T诱导的PD-L1基因表达和蛋白积累。
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