Junctional adhesion molecule 3 is a potential therapeutic target for small cell lung carcinoma
Junctional adhesion molecule 3 is a potential therapeutic target for small cell lung carcinoma
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DOI：
10.1016/j.yexcr.2023.113570
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发表时间：
2023-03-28
影响因子：
3.7
通讯作者：
Sakuma, Yuji
中科院分区：
文献类型：
--
作者：
Yamaguchi, Miki;Hirai, Sachie;Sakuma, Yuji
小细胞肺癌（SCLC）的有效治疗方法很少;因此，我们需要开发新的有效治疗方法。我们假设抗体-药物偶联物（ADC）可能是SCLC的一个有前途的选择。使用几个公开可用的数据库来证明连接粘附分子3（JAM 3）mRNA在SCLC和肺腺癌细胞系和组织中表达的程度。选择三种SCLC细胞系Lu-135、SBC-5和Lu-134 A，并通过流式细胞术检查JAM 3蛋白表达。最后，我们检查了三种SCLC细胞系对抗JAM 3单克隆抗体HSL 156（内部开发）和重组蛋白DT 3C之间的缀合物的反应，DT 3C由缺乏受体结合结构域但含有链球菌蛋白G的C1、C2和C3结构域的白喉毒素组成。计算机模拟结果显示，JAM 3 mRNA在SCLC细胞系和组织中的表达高于肺腺癌。正如所预期的，所有三种SCLC细胞系在mRNA和蛋白质水平上对JAM 3均呈阳性。因此，对照SCLC细胞，而不是JAM 3沉默的细胞，对HSL 156-DT 3C缀合物高度敏感，导致剂量和时间依赖性的活力降低。最后，单独沉默JAM 3抑制了所有检查的SCLC细胞系的生长。总之，这些发现表明靶向JAM 3的ADC可能代表治疗SCLC患者的新方法。
There are few effective therapies for small cell lung carcinoma (SCLC); thus, we need to develop novel and efficacious treatments. We hypothesized that an antibody-drug conjugate (ADC) could be a promising option for SCLC. Several publicly available databases were used to demonstrate the extent to which junctional adhesion molecule 3 (JAM3) mRNA was expressed in SCLC and lung adenocarcinoma cell lines and tissues. Three SCLC cell lines, Lu-135, SBC-5, and Lu-134 A, were selected and examined for JAM3 protein expression by flow cytometry. Finally, we examined the response of the three SCLC cell lines to a conjugate between an anti-JAM3 monoclonal antibody HSL156 (developed in-house) and the recombinant protein DT3C, which consists of diphtheria toxin lacking the receptor-binding domain but containing the C1, C2, and C3 domains of streptococcal protein G. In silico analyses revealed that JAM3 mRNA was expressed higher in SCLC cell lines and tissues than in those of lung adenocarcinoma. As expected, all the three SCLC cell lines examined were positive for JAM3 at the mRNA and protein levels. Consequently, control SCLC cells, but not JAM3-silenced ones, were highly sensitive to HSL156-DT3C conjugates, resulting in dose-and time-dependent decreased viability. Finally, silencing JAM3 alone suppressed the growth of all SCLC cell lines examined. Taken together, these findings suggest that an ADC targeting JAM3 could represent a new approach to treating SCLC patients.