Shulepko Mikhail A, Bychkov Maxim L, Shlepova Olga V, Shenkarev Zakhar O, Kirpichnikov Mikhail P, Lyukmanova Ekaterina N
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 119997 Moscow, Russian Federation.
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 119997 Moscow, Russian Federation; Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russian Federation.
Int Immunopharmacol. 2020 Feb 24;82:106303. doi: 10.1016/j.intimp.2020.106303.
Human Ly-6/uPAR-related protein-1 (SLURP-1) is an allosteric negative modulator of the α7-type nicotinic acetylcholine receptor (α7-nAChR), one of the key receptors promoting nicotine-induced proliferation of lung cancer cells. Incubation of lung adenocarcinoma A549 cells with recombinant SLURP-1 (rSLURP-1) at concentrations >10 nM resulted in the significant decrease of the cell growth (~70%), while treatment of normal lung-derived WI-38 fibroblasts with rSLURP-1 did not influence the cell proliferation up to 1 μM of the protein. rSLURP-1 fully abolished the nicotine-induced increase of the cell proliferation, down-regulation of the expression of PTEN (the negative regulator of the AKT pathway, controlling the growth, survival, and proliferation of cancer cells), and up-regulation of the α7-nAChR expression in the A549 cells. Using the siRNA against α7-nAChR and inhibitors of different cell-surface receptors, we showed that rSLURP-1 antiproliferative effect in A549 cells is connected with α7-nAChR, epidermal growth factor receptors, and β-adrenergic receptors. Moreover, we found that downstream effectors of rSLURP-1 are IP receptors and the STAT3 transcription factor. Implication of the IP receptors and PTEN in the rSLURP-1 antiproliferative activity points on the AKT-mediated signaling pathway. Co-application of rSLURP-1 with gefitinib and bortezomib (currently used anticancer drugs) resulted in an additive suppression of the A549 cells proliferation up to ~44% and 35%, respectively. Thus, rSLURP-1 could be considered a promising prototype of drugs to prevent nicotine-induced pathologies and cancer treatment.
人淋巴细胞抗原6/尿激酶型纤溶酶原激活物受体相关蛋白1（SLURP-1）是α7型烟碱型乙酰胆碱受体（α7-nAChR）的变构负调节剂，α7-nAChR是促进尼古丁诱导肺癌细胞增殖的关键受体之一。用浓度>10 nM的重组SLURP-1（rSLURP-1）孵育肺腺癌A549细胞，导致细胞生长显著降低（约70%），而用rSLURP-1处理正常肺来源的WI-38成纤维细胞，在蛋白浓度达1 μM时对细胞增殖没有影响。rSLURP-1完全消除了尼古丁诱导的A549细胞增殖增加、PTEN（AKT途径的负调节因子，控制癌细胞的生长、存活和增殖）表达下调以及α7-nAChR表达上调。使用针对α7-nAChR的小干扰RNA（siRNA）和不同细胞表面受体的抑制剂，我们表明rSLURP-1在A549细胞中的抗增殖作用与α7-nAChR、表皮生长因子受体和β-肾上腺素能受体有关。此外，我们发现rSLURP-1的下游效应器是肌醇三磷酸（IP）受体和信号转导与转录激活因子3（STAT3）转录因子。IP受体和PTEN参与rSLURP-1的抗增殖活性表明其作用于AKT介导的信号通路。rSLURP-1与吉非替尼和硼替佐米（目前使用的抗癌药物）联合应用分别导致A549细胞增殖的附加抑制，高达约44%和35%。因此，rSLURP-1可被视为预防尼古丁诱导的病变和癌症治疗的有前景的药物原型。
