Arsenic is a well-established human carcinogen associated with cancers of the skin, liver, lung, kidney, and bladder. Although numerous carcinogenic pathways have been proposed, the molecular mechanisms underlying arsenic-associated cancer etiology are still elusive. The cellular responses to arsenic exposure are dose dependent. It was recently shown that low-dose arsenic leads to a metabolic shift from mitochondrial respiration to aerobic glycolysis via inactivation of tumor suppressor p53 and activation of NF-κB. However, how inactivation of p53, activation of NF-κB, and metabolic change are coordinated in response to low-dose arsenic exposure is still not completely understood. Polo-like kinase 1 (Plk1) is a well- documented regulator in many cell cycle-related events. Herein, we showed that low-dose arsenic leads to elevation of Plk1 in an NF-κB-dependent manner and that elevation of Plk1 contributes to the metabolic change from oxidative phosphorylation to glycolysis via activation of the PI3K/AKT/mTOR pathway. Furthermore, we showed that inhibition/depletion of Plk1 reverses low-dose arsenic-associated phenotypes, including enhanced cell proliferation, activation of the PI3K/AKT/mTOR pathway, and increased glycolysis. Finally, inhibition of the PI3K/AKT/mTOR pathway also antagonizes the enhanced glycolytic influx due to low-dose arsenic exposure. Our studies support the notion that Plk1 likely plays a critical role in cellular responses to low-dose arsenic.
Keywords: NF-κB; PI3K/AKT/mTOR pathway; Plk1; low-dose arsenic; metabolic shift.