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The SRPK inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (SRPIN340) increases the immune response against metastatic melanoma in mice
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2022-07-02 , DOI: 10.1016/j.bcp.2022.115161 Gabriela Alves Moreira 1 , Mônica Maria Magalhães Caetano 1 , Juliana Alves do Vale 2 , Janine Cerqueira de Paiva 1 , Victor Hugo Sousa Gonçalves 1 , Alisson Andrade Almeida 1 , Lucas Viana Gomes Silva 1 , Fernanda Rebellato Giordano Martim 1 , Marcus Vinícius de Andrade Barros 3 , Gabriela Rapozo Guimarães 4 , Leandro de Oliveira Santos 4 , Ana Paula Martins de Souza 3 , Mariana Machado-Neves 2 , Róbson Ricardo Teixeira 3 , Abelardo Silva-Júnior 5 , Juliana Lopes Rangel Fietto 1 , Mariana Boroni 4 , Leandro Licursi de Oliveira 2 , Gustavo Costa Bressan 1
BIOCHEMICAL PHARMACOLOGY ( IF 5.3 ) Pub Date : 2022-07-02 , DOI: 10.1016/j.bcp.2022.115161 Gabriela Alves Moreira 1 , Mônica Maria Magalhães Caetano 1 , Juliana Alves do Vale 2 , Janine Cerqueira de Paiva 1 , Victor Hugo Sousa Gonçalves 1 , Alisson Andrade Almeida 1 , Lucas Viana Gomes Silva 1 , Fernanda Rebellato Giordano Martim 1 , Marcus Vinícius de Andrade Barros 3 , Gabriela Rapozo Guimarães 4 , Leandro de Oliveira Santos 4 , Ana Paula Martins de Souza 3 , Mariana Machado-Neves 2 , Róbson Ricardo Teixeira 3 , Abelardo Silva-Júnior 5 , Juliana Lopes Rangel Fietto 1 , Mariana Boroni 4 , Leandro Licursi de Oliveira 2 , Gustavo Costa Bressan 1
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Cancers have a strong relationship with immune cells in their microenvironment, which significantly influences tumor proliferation and progression. Thus, pharmacological strategies that stimulate the immune system to combat tumor cells are promising for better therapeutic efficacy. Deregulated expression of the splicing regulatory serine arginine protein kinases (mostly SRPK1 and SRPK2) has been found in different cancer types, leading to the expression of isoforms related to tumor growth and metastasis. The microenvironment of melanoma exhibits a strong presence of immune cells, which significantly influences tumor progression, and around 50% of cutaneous melanoma patients benefit from targeted immunotherapy. Here, we analyzed human malignant melanoma single-cell gene expression data and observed that SRPK1/2 overexpression correlates with immune system pathway alterations. In further analysis, we observed an increased presence of immune cells in biopsies from mice bearing metastatic melanoma treated with SRPIN340, a well-known SRPK1/2 pharmacological inhibitor. Local treatments increased the expression of proinflammatory cytokines at the tumor lesions and the activity of the spleen, accompanied by reduced pulmonary metastasis foci, edema formation, and alveolar congestion. In assays, SRPIN340 also potentiated immunological susceptibility, by increasing the expression of the antigen presenting MHCI and MHCII molecules and by increasing the ability of B16F10 cells to attract splenic cells in transwell assays. Taken together, these results reveal that the antimetastatic effect of SRPIN340 can also involve an increased immune response, which suggests additional functional clues for SRPKs in tumor biology.
中文翻译：
SRPK 抑制剂 N-(2-(哌啶-1-基)-5-(三氟甲基)苯基)异烟酰胺 (SRPIN340) 增强小鼠针对转移性黑色素瘤的免疫反应
癌症与其微环境中的免疫细胞有很强的关系，这显着影响肿瘤的增殖和进展。因此，刺激免疫系统对抗肿瘤细胞的药理学策略有望获得更好的治疗效果。在不同的癌症类型中发现了剪接调节性丝氨酸精氨酸蛋白激酶（主要是SRPK1和SRPK2）的表达失调，导致与肿瘤生长和转移相关的亚型的表达。黑色素瘤的微环境中存在大量免疫细胞，这显着影响肿瘤进展，约 50% 的皮肤黑色素瘤患者受益于靶向免疫治疗。在这里，我们分析了人类恶性黑色素瘤单细胞基因表达数据，并观察到 SRPK1/2 过度表达与免疫系统通路改变相关。在进一步的分析中，我们观察到接受 SRPIN340（一种著名的 SRPK1/2 药理学抑制剂）治疗的转移性黑色素瘤小鼠的活检组织中免疫细胞的存在增加。局部治疗增加了肿瘤病灶处促炎细胞因子的表达和脾脏的活性，同时减少了肺转移灶、水肿形成和肺泡充血。在检测中，SRPIN340 还通过增加抗原呈递 MHCI 和 MHCII 分子的表达以及通过增加 B16F10 细胞在 Transwell 检测中吸引脾细胞的能力来增强免疫敏感性。总而言之，这些结果表明 SRPIN340 的抗转移作用还可能涉及增强的免疫反应，这表明 SRPK 在肿瘤生物学中的其他功能线索。
更新日期：2022-07-02
中文翻译：
SRPK 抑制剂 N-(2-(哌啶-1-基)-5-(三氟甲基)苯基)异烟酰胺 (SRPIN340) 增强小鼠针对转移性黑色素瘤的免疫反应
癌症与其微环境中的免疫细胞有很强的关系，这显着影响肿瘤的增殖和进展。因此，刺激免疫系统对抗肿瘤细胞的药理学策略有望获得更好的治疗效果。在不同的癌症类型中发现了剪接调节性丝氨酸精氨酸蛋白激酶（主要是SRPK1和SRPK2）的表达失调，导致与肿瘤生长和转移相关的亚型的表达。黑色素瘤的微环境中存在大量免疫细胞，这显着影响肿瘤进展，约 50% 的皮肤黑色素瘤患者受益于靶向免疫治疗。在这里，我们分析了人类恶性黑色素瘤单细胞基因表达数据，并观察到 SRPK1/2 过度表达与免疫系统通路改变相关。在进一步的分析中，我们观察到接受 SRPIN340（一种著名的 SRPK1/2 药理学抑制剂）治疗的转移性黑色素瘤小鼠的活检组织中免疫细胞的存在增加。局部治疗增加了肿瘤病灶处促炎细胞因子的表达和脾脏的活性，同时减少了肺转移灶、水肿形成和肺泡充血。在检测中，SRPIN340 还通过增加抗原呈递 MHCI 和 MHCII 分子的表达以及通过增加 B16F10 细胞在 Transwell 检测中吸引脾细胞的能力来增强免疫敏感性。总而言之，这些结果表明 SRPIN340 的抗转移作用还可能涉及增强的免疫反应，这表明 SRPK 在肿瘤生物学中的其他功能线索。
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