Dysregulation of mitochondrial function by PLK1-mediated PDHA1 phosphorylation promotes Cr(VI)-associated lung cancer progression

Abstract

SummaryHexavalent chromium (Cr(VI)) is a class I environmental carcinogen known to induce lung epithelial cell transformation and promote lung cancer progression through alterations in the cell cycle and cellular energy metabolism. In this study, we investigated the role of polo-like kinase 1 (PLK1) in Cr(VI)-transformed (CrT) bronchial epithelial cells (BEAS-2B) and found that PLK1 expression was significantly upregulated in CrT cells, leading to impaired mitochondrial function and enhanced cell proliferation both in vitro and in vivo. High levels of PLK1 in CrT cells resulted in decreased mitochondrial activity due to defective modulation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), which is crucial for pyruvate/Acetyl-CoA conversion and carbon influx into the tricarboxylic acid (TCA) cycle. Mechanistically, we demonstrated that PLK1 directly phosphorylates PDHA1 at T57, leading to E1 collapse and PDHA1 degradation via activation of mitophagy. These defects resulted in the inhibition of oxidative phosphorylation and reduction of mitochondrial superoxide generation, ultimately leading to suppression of mitochondrial-mediated apoptotic response. Our findings highlight the role of PLK1 in metabolic reprogramming during Cr(VI)-associated cancer progression, providing new insights and a potential therapeutic target to inhibit Cr(VI)-induced cancer development. Moreover, PLK1 inhibitors may also have the potential to increase chemo-sensitivity of cancer cells by restoring normal mitochondrial function, thereby mitigating drug resistance caused by mitochondrial dysfunction and hyperpolarization.