Abstract
Hexavalent chromium [Cr(VI)] compounds are well established human lung carcinogens, but it is unknown how they cause lung cancer in humans. Recent data indicate that Cr(VI) induces chromosome instability in human lung cells, and genomic instability is considered a leading mechanism to explain chromate carcinogenesis. The Spindle Assembly Checkpoint (SAC) is a critical regulator of the metaphase-to-anaphase transition and ensures genome stability by preventing chromosomal missegregation events. Bypass of the SAC can lead to genomic instability, manifested as aneuploidy, which eventually leads to tumor formation and cancer. Recent studies in our laboratory demonstrated that chronic exposure to zinc chromate induces SAC bypass in a concentration- and time-dependent manner in human lung fibroblasts. To further study these events, we focused on the cell division cycle 20 (Cdc20) protein, a downstream effector protein in the SAC. Cdc20 has not been studied after Cr(VI) exposure, but other studies show that experimentally induced alterations of Cdc20 localization to kinetochores or of Cdc20 protein expression leads to aneuploidy. Here, we investigated the effects of zinc chromate, a particulate Cr(VI) compound, on Cdc20 localization, protein expression and interactions. Our data show Cdc20 is a target for particulate Cr(VI). Chronic zinc chromate exposure altered Cdc20 kinetochore localization and reduced the interaction of phosphorylated Cdc20 with Mad2, which may underlie zinc chromate-induced SAC bypass.
Highlights
Hexavalent chromium [Cr(VI)] is a known human lung carcinogen and the solubility of Cr(VI) plays an important role in its carcinogenicity [1,2,3]
During spindle assembly checkpoint (SAC) activation in mitosis, cell division cycle 20 (Cdc20) localizes to unattached kinetochores binding with other checkpoint proteins and enzymes to inhibit the metaphase to anaphase transition [19,20,21]
We evaluated the impact of zinc chromate on Cdc20 localization
Summary
Hexavalent chromium [Cr(VI)] is a known human lung carcinogen and the solubility of Cr(VI) plays an important role in its carcinogenicity [1,2,3]. Epidemiologic studies show a higher lung cancer risk for particulate- Cr(VI)-exposed workers [2], and experimental studies show that only particulate Cr(VI) compounds induce tumors in animal models and neoplastic transformation of cultured mouse embryo cells [2,4]. Chromosome Instability (CIN) consisting of alterations of both chromosome number and structure is a hallmark of human lung cancer [5]. Cell culture studies show that both particulate and soluble Cr(VI) compounds can induce CIN in human lung cells and that human bronchial epithelial cells malignantly transformed by Cr(VI) exhibit an aneuploid phenotype [6,7]. Further data show that mechanisms underlying Cr(VI)-induced numerical CIN involve centrosome amplification and bypass of the spindle assembly checkpoint (SAC) [7,8]
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