Airborne particulate matter induces mitotic slippage and chromosomal missegregation through disruption of the spindle assembly checkpoint (SAC)

Abstract Particulate matter (PM) is a risk factor for lung cancer development and chromosomal missegregation and cell cycle disruptions are key cellular events that trigger tumorigenesis. We aimed to study the effect of PM 10 (PM with an aerodynamic diameter ≤10 μm) on mitotic arrest and chromosomal segregation, evaluating the spindle assembly checkpoint (SAC) protein dynamics in the human lung A549 adenocarcinoma cell line. For this purpose, synchronized cells were exposed to PM 10 for 24 h to obtain the frequency of micronucleated (MN) and trinucleated (TN) cells. Then, the efficiency of the mitotic arrest after PM 10 exposure was analyzed. To elucidate the effect of PM 10 in chromosomal segregation, the levels and subcellular localization of essential SAC proteins were evaluated. Results indicated that A549 cells exposed to PM 10 exhibited an increase in MN and TN cells and a decrease in mitotic indexes and G2/M phase. A549 cells treated with PM 10 showed reduced protein levels of MDC1 and NEK2 (38% and 35% respectively), which is required for MAD2 recruitment to kinetochores, MAD2 and BUBR1, effectors of the SAC (25% and 18% respectively), and CYCLIN B1, required during G2/M phase (35%). Besides, PM 10 exposure increase the levels of AURORA B and SURVIVIN, required for SAC activation through chromosome-microtubule attachment errors (85% and 74% respectively). We suggest that PM 10 causes mitotic slippage due to alterations in MAD2 localization. Thus, PM 10 causes inadequate chromosomal segregation and deficient mitotic arrest by altering SAC protein levels, predisposing A549 cells to chromosomal instability, a common feature observed in cancer.