Hexavalent chromium induces centrosome amplification through ROS‐ATF6‐PLK4 pathway in colon cancer cells

• Published in: Cell biology international Vol. 46; no. 7; pp. 1128 - 1136
• Main Authors: Bian, Xue K., Guo, Jia L., Xu, Si X., Han, Ya W., Lee, Shao C., Zhao, Ji Z.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2022
• Subjects: Acetylcysteine; ATF6; Carcinogens; centrosome amplification; Centrosomes; Chromium; Colon cancer; Colorectal cancer; Endoplasmic reticulum; hexavalent chromium; Invasiveness; Metastases; Metastasis; PLK4; Proteins; Reactive oxygen species; ROS; signaling pathway; siRNA; Tumorigenesis; PLK4; centrosome amplification; signaling pathway; hexavalent chromium; ATF6; ROS
• ISSN: 1065-6995; 1095-8355
• DOI: 10.1002/cbin.11791

Centrosome amplification (CA) refers to a numerical increase in centrosomes resulting in cells with more than two centrosomes. CA has been shown to initiate tumorigenesis and increase the invasive potential of cancer cells in genetically modified experimental models. Hexavalent chromium is a recognized carcinogen that causes CA and tumorigenesis as well as promotes cancer metastasis. Thus, CA appears to be a biological link between chromium and cancer. In the present study, we investigated how chromium triggers CA. Our results showed that a subtoxic concentration of chromium‐induced CA in HCT116 colon cancer cells, resulted in the production of reactive oxygen species (ROS), activated ATF6 without causing endoplasmic reticulum stress, and upregulated the protein level of PLK4. Inhibition of ROS production, ATF6 activation, or PLK4 upregulation attenuated CA. Inhibition of ROS using N‐acetyl‐l‐cysteine (NAC) inhibited chromium‐induced activation of ATF6 and upregulation of PLK4. ATF6‐specific siRNA knocked down the protein level and activation of ATF6, and upregulated PLK4, with no effect on ROS production. Knockdown of PLK4 protein had no effect on chromium‐induced ROS production or activation of ATF6. In conclusion, our results suggest that hexavalent chromium induces CA via the ROS‐ATF6‐PLK4 pathway and provides molecular targets for inhibiting chromium‐mediated CA, which may be useful for the assessment of CA in chromium‐promoted tumorigenesis and cancer cell metastasis.