Effect of zinc oxide nanomaterials-induced oxidative stress on the p53 pathway

Excessive production of reactive oxygen species (ROS) is a hallmark feature in nanomaterials (NMs) induced cellular toxicity. However, the inter-relationship between NMs induced ROS generation and the cells innate ability to regulate intracellular ROS level in effecting a particular cellular outcome is currently underexplored. Here, using a BJ fibroblast p53 knockdown system, we showed that p53 may be implicated in playing a dual regulatory role to determine cell survivability in response to oxidative stress induced by ZnO NMs. At low level of ZnO NMs induced ROS, p53 triggers expression of antioxidant genes such as SOD2, GPX1, SESN1, SESN2 and ALDH4A1 to restore oxidative homeostasis while at high concentration of ZnO NMs, the elevated level of intracellular ROS activated the apoptotic pathway through p53. The implication of our finding that p53 can function as an important regulator in determining ZnO induced cytotoxicity is highlighted by the differential action of ZnO on p53 deficient and proficient colorectal cell lines. p53 deficient cells cancer cells such as DLD-1 and SW480 are more susceptible to ZnO induced cell death compared to p53 proficient cells such as colon epithelial cells NCM460 and HCT116 cells in a ROS dependent manner. Collectively, our findings showcased a role p53 plays in the context of nanotoxicity and highlights the need to consider the interplay of physicochemical properties of NMs and cell biology.