Koomoa Dana-Lynn T, Sunada Nathan, Espinoza-Fuenzalida Italo, Tacdol Dustin, Shackleford Madeleine, Feng Li, Sun Dianqing, Lange Ingo
College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 01119, USA.
The Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, Hilo, HI 96720, USA.
Int J Mol Sci. 2025 Mar 29;26(7):3180. doi: 10.3390/ijms26073180.
High-risk neuroblastoma (HRNB) is an extracranial solid pediatric cancer. Despite the plethora of treatments available for HRNB, up to 65% of patients are refractory or exhibit an initial response to treatment that transitions to therapy-resistant relapse, which is invariably fatal. A key feature that promotes HRNB progression is aberrant calcium (Ca) signaling. Ca signaling is regulated by several druggable channel proteins, offering tremendous therapeutic potential. Unfortunately, many of the Ca channels in HRNB also perform fundamental functions in normal healthy cells, hence targeting them increases the potential for adverse effects. To overcome this challenge, we sought to identify novel Ca signaling pathways that are observed in HRNB but not normal non-cancerous cells with the hypothesis that these novel pathways may serve as potential therapeutic targets. One Ca signaling pathway that is deregulated in HRNB is store-operated Ca entry (SOCE). SOCE relays the release of Ca from the endoplasmic reticulum (ER) and Ca influx via the plasma membrane and promotes cancer drug resistance by regulating transcriptional programming and the induction of mitochondrial Ca (mtCa)-dependent signaling. mtCa signaling is critical for cellular metabolism, reactive oxygen production, cell cycle, and proliferation and has a key role in the regulation of cell death. Therefore, a dynamic interplay between ER, SOCE, and mitochondria tightly regulates cell survival and apoptosis. From a library of synthesized novel molecules, we identified two structurally related compounds that uniquely disrupt the dynamic interplay between SOCE, ER, and mitochondrial signaling pathways and induce cell death in HRNB. Our results revealed that compounds and activate distinct aberrant Ca signals that are unique to relapsed HRNB and could be exploited to induce mtCa overload, a novel calcium influx current, and subsequent cell death. These findings establish a potential new pathway of calcium-mediated cell death; targeting this pathway could be critical for the treatment of refractory and relapsed HRNB.
高危神经母细胞瘤（HRNB）是一种儿童颅外实体癌。尽管有大量针对HRNB的治疗方法，但仍有高达65%的患者对治疗无效或最初对治疗有反应，但随后转变为治疗抵抗性复发，这往往是致命的。促进HRNB进展的一个关键特征是异常的钙（Ca）信号传导。Ca信号传导由几种可药物靶向的通道蛋白调节，具有巨大的治疗潜力。不幸的是，HRNB中的许多Ca通道在正常健康细胞中也发挥着基本功能，因此靶向它们会增加产生不良反应的可能性。为了克服这一挑战，我们试图识别在HRNB中而非正常非癌细胞中观察到的新型Ca信号通路，假设这些新型通路可能作为潜在的治疗靶点。在HRNB中失调的一种Ca信号通路是储存性钙内流（SOCE）。SOCE通过内质网（ER）释放Ca并通过质膜进行Ca内流来传递信号，并通过调节转录程序和诱导线粒体Ca（mtCa）依赖性信号传导来促进癌症耐药性。mtCa信号传导对细胞代谢、活性氧产生、细胞周期和增殖至关重要，并且在细胞死亡的调节中起关键作用。因此，内质网、SOCE和线粒体之间的动态相互作用紧密调节细胞存活和凋亡。从合成的新型分子库中，我们鉴定出两种结构相关的化合物，它们独特地破坏了SOCE、内质网和线粒体信号通路之间的动态相互作用，并在HRNB中诱导细胞死亡。我们的结果表明，化合物 和 激活了复发HRNB特有的独特异常Ca信号，可利用这些信号诱导mtCa过载、一种新型钙内流电流以及随后的细胞死亡。这些发现建立了一种潜在的钙介导细胞死亡新途径；靶向该途径可能对难治性和复发性HRNB的治疗至关重要。
