Odarenko Kirill V, Salomatina Oksana V, Chernikov Ivan V, Salakhutdinov Nariman F, Zenkova Marina A, Markov Andrey V
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia.
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia.
Pharmaceuticals (Basel). 2023 Sep 27;16(10):1369. doi: 10.3390/ph16101369.
Despite the proven tumorigenic effect of leptin on epithelial-derived cancers, its impact on the aggressiveness of neural crest-derived cancers, notably neuroblastoma, remains largely unexplored. In our study, for the first time, transcriptome analysis of neuroblastoma tissue demonstrated that the level of leptin is elevated in neuroblastoma patients along with the severity of the disease and is inversely correlated with patient survival. The treatment of murine Neuro2a neuroblastoma cells with leptin significantly stimulated their proliferation and motility and reduced cell adhesion, thus rendering the phenotype of neuroblastoma cells more aggressive. Given the proven efficacy of cyanoenone-bearing semisynthetic triterpenoids in inhibiting the growth of neuroblastoma and preventing obesity in vivo, the effect of soloxolone methyl (SM) on leptin-stimulated Neuro2a cells was further investigated. We found that SM effectively abolished leptin-induced proliferation of Neuro2a cells by inducing G1/S cell cycle arrest and restored their adhesiveness to extracellular matrix (ECM) proteins to near control levels through the upregulation of vimentin, zonula occludens protein 1 (ZO-1), cell adhesion molecule L1 (, and neural cell adhesion molecule 1 (. Moreover, SM significantly suppressed the leptin-associated phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and ribosomal protein S6 kinase A1 (p90RSK), which are key kinases that ensure the survival and proliferation of cancer cells. Further molecular modeling studies demonstrated that the inhibitory effect of SM on the mitogen-activated protein kinase (MAPK)/ERK1/2 signaling pathway can be mediated by its direct interaction with ERK2 and its upstream regulators, son of sevenless homolog 1 (SOS) and mitogen-activated protein kinase kinase 1 (MEK1). Taken together, our findings in murine Neuro2a cells provide novel evidence of the stimulatory effect of leptin on the aggressiveness of neuroblastoma, which requires further detailed studies in human neuroblastoma cells and relevant animal models. The obtained results indicate that SM can be considered a promising drug candidate capable of reducing the impact of adipokines on tumor progression.
尽管瘦素对上皮来源的癌症具有已被证实的致瘤作用，但其对神经嵴来源的癌症（尤其是神经母细胞瘤）侵袭性的影响在很大程度上仍未得到探索。在我们的研究中，首次对神经母细胞瘤组织进行转录组分析表明，神经母细胞瘤患者体内瘦素水平随疾病严重程度升高，且与患者生存率呈负相关。用瘦素处理小鼠Neuro2a神经母细胞瘤细胞可显著刺激其增殖和迁移，并降低细胞黏附，从而使神经母细胞瘤细胞的表型更具侵袭性。鉴于含氰基烯酮的半合成三萜类化合物在体内抑制神经母细胞瘤生长和预防肥胖方面已被证实有效，进一步研究了甲基索洛酮（SM）对瘦素刺激的Neuro2a细胞的作用。我们发现，SM通过诱导G1/S期细胞周期阻滞有效消除了瘦素诱导的Neuro2a细胞增殖，并通过上调波形蛋白、闭合蛋白1（ZO-1）、细胞黏附分子L1（ ）和神经细胞黏附分子1（ ），将其与细胞外基质（ECM）蛋白的黏附恢复到接近对照水平。此外，SM显著抑制了与瘦素相关的细胞外信号调节激酶1/2（ERK1/2）和核糖体蛋白S6激酶A1（p90RSK）的磷酸化，这两种激酶是确保癌细胞存活和增殖的关键激酶。进一步的分子模拟研究表明，SM对丝裂原活化蛋白激酶（MAPK）/ERK1/2信号通路的抑制作用可通过其与ERK2及其上游调节因子七号无翅型同源物1（SOS）和丝裂原活化蛋白激酶激酶1（MEK1）的直接相互作用来介导。综上所述，我们在小鼠Neuro2a细胞中的研究结果为瘦素对神经母细胞瘤侵袭性的刺激作用提供了新的证据，这需要在人类神经母细胞瘤细胞和相关动物模型中进行进一步详细研究。所得结果表明，SM可被视为一种有前景的候选药物，能够降低脂肪因子对肿瘤进展的影响。
