Chronic Exposure to Particulate Chromate Induces Spindle Assembly Checkpoint Bypass in Human Lung Cells

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• 作者：Sandra S. Wise ; Amie L. Holmes ; Hong Xie ; W. Douglas Thompson ; John Pierce Wise ; Sr.
• 刊名：Chemical Research in Toxicology
• 出版年：2006
• 出版时间：November 2006
• 年：2006
• 卷：19
• 期：11
• 页码：1492 - 1498
• 全文大小：504K
• 年卷期：v.19,no.11(November 2006)
• ISSN：1520-5010

文摘

One of the hallmarks of lung cancer is chromosome instability (CIN), particularly a tetraploid phenotype,which is normally prevented by the spindle assembly checkpoint. Hexavalent chromium [Cr(VI)] is anestablished human lung carcinogen, and Cr(VI) induces tumors at lung bifurcation sites where Cr(VI)particles impact and persist. However, the effects of Cr(VI) on the spindle assembly checkpoint areunknown and little is known about prolonged exposure to particulate Cr(VI). Accordingly, we investigatedparticulate Cr(VI)-induced bypass of the spindle assembly checkpoint after several days of exposure inWHTBF-6 cells. We found that lead chromate indeed induces spindle assembly checkpoint bypass inhuman lung cells, as 72, 96, and 120 h treatments with 0.5 or 1 ges/entities/mgr.gif">g/cm² lead chromate induced significantincreases in the percentage of cells with aberrant mitotic figures. For example, treatment with 1 ges/entities/mgr.gif">g/cm²lead chromate for 96 h induced 11, 12.3, and 14% of cells with premature anaphase, centromere spreadingand premature centromere division, respectively. In addition, we found a disruption of mitosis with morecells accumulating in anaphase; cells treated for 96 h increased from 18% in controls to 31% in cellstreated with lead chromate. To confirm involvement of the spindle assembly checkpoint, Mad2 expressionwas used as a marker. Mad2 expression was decreased in cells exposed to chronic treatments of leadchromate, consistent with disruption of the checkpoint. We also found concentration- and time-dependentincreases in tetraploid cells, which continued to grow and form colonies. When cells were treated withchronic lead alone there was no increase in aberrant mitotic cells or polyploidy; however, chronic exposureto a soluble Cr(VI) showed an increase in aberrant mitotic cells and polyploidy. These data suggest thatlead chromate does induce CIN and may be one mechanism in the development of Cr(VI)-induced lungcancer.