The tobacco carcinogen NNK disturbs mitotic chromosome alignment by interrupting p53 targeting to the centrosome

Abstract

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most potent risk factor among tobacco-related carcinogens in lung cancer progression and outcomes. Although genetic mutations and chromosome instability have been detected in NNK-induced lung tumors, the oncogenic mechanisms of NNK are not fully understood. Here, we show that NNK increases chromosomal instability by disrupting spindle microtubule (MT) attachment to the kinetochore (KT) and spindle dynamics. Mechanistically, NNK blocks the targeting of p53 to the centrosome during mitosis, leading to chromosome alignment defects in metaphase. Therefore, lung cancer cells with wild-type p53, such as A594 and H226B, are more resistant to the NNK treatment than p53-mutant lung cancer cells, such as A1299 and H226Br. Although NNK does not affect the levels or transcriptional activity of p53, the reduction of the p53 level at the centrosome exacerbates the NNK-induced chromosome alignment defect in A549 and H226B cells. Therefore, p53 protects against NNK-induced chromosome instability by modulating the function of centrosome-localized p53 and not by modulating transcriptional activity. We conclude that NNK may increase the risk of lung cancer progression and poorer outcomes in patients with p53 mutations by perturbing proper mitotic progression and chromosome integrity.