Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA.
Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, 78229, USA.
Oncogene. 2022 Aug;41(33):4042-4054. doi: 10.1038/s41388-022-02410-x. Epub 2022 Jul 14.
LKB1 loss of function is one key oncogenic event in lung cancer. Clinical data suggest that LKB1 loss of function is associated with patients' smoking status. The responsible ingredients and molecular mechanisms in tobacco for LKB1 loss of function, however, are not defined. In this study, we reported that NNAL, a major metabolite of a tobacco-specific carcinogen NNK, induces LKB1 phosphorylation and its loss of function via the β-AR/PKA signaling pathway in an isomer-dependent manner in human lung cancer cells. NNAL exposure also resulted in enhanced lung cancer cell migration and chemoresistance in an LKB1-dependent manner. A 120-day NNAL exposure in lung cancer cells, mimicking its chronic exposure among smokers, resulted in more prominent LKB1 phosphorylation, cell migration, and chemoresistance even in the absence of NNAL, indicating the long-lasting LKB1 loss of function although such an effect eventually disappeared after NNAL was removed for two months. These observations were confirmed in a lung cancer xenograft model. More importantly, human lung cancer tissues revealed elevated LKB1 phosphorylation in comparison to the paired normal lung tissues. These results suggest that LKB1 loss of function in human lung cancer could be extended to its phosphorylation, which may be mediated by NNAL from tobacco smoke in an isomer-dependent manner via the β-AR/PKA signaling pathway.
LKB1 功能丧失是肺癌的一个关键致癌事件。临床数据表明，LKB1 功能丧失与患者的吸烟状况有关。然而，烟草中导致 LKB1 功能丧失的责任成分和分子机制尚不清楚。在这项研究中，我们报道了 NNAL，一种烟草特异性致癌原 NNK 的主要代谢物，以依赖异构体的方式通过β-AR/PKA 信号通路诱导人肺癌细胞中 LKB1 的磷酸化及其功能丧失。NNAL 暴露还以依赖于 LKB1 的方式增强肺癌细胞的迁移和化疗耐药性。在肺癌细胞中进行为期 120 天的 NNAL 暴露，模拟吸烟者的慢性暴露，即使在没有 NNAL 的情况下，也会导致更明显的 LKB1 磷酸化、细胞迁移和化疗耐药性，尽管这种效应在两个月后 NNAL 被去除后最终消失。这些观察结果在肺癌异种移植模型中得到了证实。更重要的是，与配对的正常肺组织相比，人类肺癌组织中 LKB1 的磷酸化水平升高。这些结果表明，人类肺癌中 LKB1 的功能丧失可能扩展到其磷酸化，这可能是通过β-AR/PKA 信号通路由烟草烟雾中的 NNAL 以依赖异构体的方式介导的。
