Hexavalent chromium induces amplification via ROS‐TF6‐PLK4 pathway

Abstract

Hexavalent chromium is classified as one of the group one carcinogens in 2012 by the IARC. Accumulated evidence indicates that centrosome amplification is sufficient to initiation tumorigenesis. Since chromium can cause centrosome amplification, it is logical to suspect that chromium causes tumorigenesis via centrosome amplification. The present study investigated the molecular mechanisms underlying chromium-elicited centrosome amplification using non-cancerous lung cells as an experimental model. We found that hexavalent chromium K2Cr2O7 was sub-toxic the cells at the concentration of 0.5 µM or below. At the sub-toxic concentrations, it induced centrosome amplification significantly. Treatment of the cells by chromium increased the intracellular level of reactive oxygen species (ROS), activated ATF-6, and increased the protein level of PLK4. Antioxidant N-acetylcysteine was able to inhibit the chromium-triggered ROS, ATF-6 activation, increment in PLK expression and centrosome amplification. Knockdown of ATF-6 inhibited the production of AFT6 active fragment, the PLK4 expression and centrosome amplification by chromium, without affecting the chromium-produced ROS. Knockdown of PLK4 inhibited the centrosome amplification, but did not modify the ROS production and AFT6 activation. In conclusion, our results suggest that the hexavalent chromium evokes centrosome amplification via ROS-ATF-6-PLK4 signaling pathways. Understanding the molecular mechanisms underlying the chromium-induced centrosome amplification is helpful for the assessment of centrosome amplification in the chromium-caused tumorigenesis.