Cadmium induces cell centrosome amplification via reactive oxygen species as well as endoplasmic reticulum stress pathway.

There is evidence that cadmium can initiate carcinogenesis. However, the underlying mechanisms remain unknown. There is also evidence that moderate centrosome amplification can initiate tumorigenesis. The present study investigated whether cadmium could trigger cell centrosome amplification, and examined the underlying molecular mechanisms. We found that cadmium was able to cause cell centrosome amplification at the subtoxic concentrations, in a dose-dependent manner. It could cause centrosome amplification via the signaling of reactive oxygen species (ROS). Proteomic analysis revealed that cadmium caused differential expressions of three proteins, which included HSPA1A which is associated with endoplasmic reticulum (ER) stress. Western blot analysis confirmed that cadmium upregulated HSPA1A. Further analyses showed that cadmium upregulated Bip and decreased the phosphorylation of ASK1 as well as increased the phosphorylation of MKK7 and c-Jun N-terminal kinases (JNK). Knockdown of JNK2 using small interfering RNA inhibited the cadmium-induced centrosome amplification but not the level of ROS. N-acetylcysteine did not inhibit the cadmium-activated ER stress pathway. In conclusion, our results suggest that cadmium can induce cell centrosome amplification via ROS as well as ER stress through the Bip-TRAF2-ASK1-MKK7-JNK signaling route, in parallel. More studies are required to clarify whether centrosome amplification underlies cadmium-induced carcinogenesis.