Singh Jasvinder, Sah Bindeshwar, Deng Yibin, Clarke Robert, Liu Liang
The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
Department of Urology, University of Minnesota Medical School, Minneapolis, MN, 55455, USA.
Cell Death Dis. 2025 Apr 2;16(1):236. doi: 10.1038/s41419-025-07566-4.
Thioredoxin-interacting protein (TXNIP) plays a pivotal role in glucose metabolism and redox signaling. Its emerging function as a potent suppressor of cell proliferation in various cancer contexts underscores its importance in cancer development. In a previous study, we found TXNIP activation by UNC0642, an inhibitor of histone methyltransferase G9A, significantly inhibited MDA-MB-231 breast cancer cell proliferation in vitro and tumor growth in vivo. Here, we demonstrated that TXNIP knockdown increased MDA-MB-231 tumor growth and metastasis in a mouse model. Reintroducing TXNIP into TXNIP-deficient HCC-1954 breast cancer cells decreased cell proliferation and migration while boosting the generation of reactive oxygen species, alongside reductions in mitochondrial respiration, mitochondrial membrane potential, and glycolysis. To elucidate the mechanisms underlying TXNIP's antitumor effects in breast cancer cells, we conducted co-immunoprecipitation and proteomic analyses that revealed calpastatin (CAST) as a novel TXNIP-interacting protein in MDA-MB-231 and HCC-1954 cells. Overexpression of CAST, an endogenous inhibitor of calpains, significantly increased xenograft tumor growth for both MDA-MB-231 and HCC-1954 cells, underscoring its novel role as a tumor promoter. In addition, we identified a positive correlation between the expression of TXNIP and interleukin-24 (IL-24), a molecule that induces cancer-specific apoptosis in several breast cancer cell lines. Our findings also show TXNIP's ability to decrease activation of STAT3, a key driver of oncogenesis. Finally, cells with high levels of TXNIP expression displayed increased susceptibility to IL-24 and WP1066, a specific STAT3 inhibitor, suggesting possible predictive value for TXNIP. Collectively, these findings unveil novel TXNIP-dependent pathways that may contribute to breast cancer pathogenesis, enriching our understanding of this molecule's intricate role in cancer and potentially paving the way for clinical translation.
硫氧还蛋白相互作用蛋白（TXNIP）在葡萄糖代谢和氧化还原信号传导中起关键作用。它作为多种癌症环境中细胞增殖的有效抑制剂这一新兴功能凸显了其在癌症发展中的重要性。在先前的一项研究中，我们发现组蛋白甲基转移酶G9A的抑制剂UNC0642激活TXNIP后，在体外显著抑制了MDA-MB-231乳腺癌细胞的增殖，并在体内抑制了肿瘤生长。在此，我们证明在小鼠模型中，TXNIP基因敲低会增加MDA-MB-231肿瘤的生长和转移。将TXNIP重新引入缺乏TXNIP的HCC-1954乳腺癌细胞中，可降低细胞增殖和迁移，同时增加活性氧的生成，同时线粒体呼吸、线粒体膜电位和糖酵解也会减少。为了阐明TXNIP在乳腺癌细胞中抗肿瘤作用的潜在机制，我们进行了免疫共沉淀和蛋白质组学分析，结果显示钙蛋白酶抑制蛋白（CAST）是MDA-MB-231和HCC-1954细胞中一种新的与TXNIP相互作用的蛋白质。钙蛋白酶的内源性抑制剂CAST的过表达显著增加了MDA-MB-231和HCC-1954细胞异种移植肿瘤的生长，突出了其作为肿瘤促进因子的新作用。此外，我们发现TXNIP的表达与白细胞介素-24（IL-24）之间存在正相关，IL-24是一种能在多种乳腺癌细胞系中诱导癌症特异性凋亡的分子。我们的研究结果还表明TXNIP具有降低STAT3激活的能力，STAT3是肿瘤发生的关键驱动因素。最后，TXNIP表达水平高的细胞对IL-24和特异性STAT3抑制剂WP1066表现出更高的敏感性，这表明TXNIP可能具有预测价值。总的来说，这些发现揭示了可能导致乳腺癌发病机制的新的TXNIP依赖性途径，丰富了我们对该分子在癌症中复杂作用的理解，并可能为临床转化铺平道路。
