Resveratrol activates DNA damage response through inhibition of polo-like kinase 1 (PLK1) in natural killer/T cell lymphoma

BACKGROUND: Extranodal natural killer/T cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis. Resveratrol (REV), a natural nontoxic pleiotropic agent, has antitumor effects, yet not being studied in NKTCL. METHODS: We performed immunohistochemical (IHC) staining with NKTCL tumor tissues. Apoptosis and cell cycle of NKTCL cell line NK-92 were detected by using flow cytometry. Then we detected the cellular expression level of polo-like kinase 1 (PLK1) and key molecules in DNA damage response (DDR) pathway by using RNA sequencing (RNA-seq) technology, real-time PCR, and Western blot. RESULTS: In this study, we found distinguishingly expressed phosphorylated ataxia telangiectasia mutated (ATM) in human NKTCL tumor tissues compared to normal lymph nodes samples. But low levels of phosphorylated checkpoint kinase 2 (Chk2) and phosphorylated p53 were shown, suggesting that DDR pathway is blocked midway in NKTCL. REV inhibited the proliferation of NK-92 cells in a time- and dose-dependent manner, arrested cell cycle at G1 phase, and induced mitochondrial apoptosis. PLK1 was inhibited in both mRNA and protein levels by REV in NK-92 cells. At the same time, phosphorylation levels of Chk2 and p53 were upregulated. CONCLUSIONS: DDR pathway plays an important role in the pathogenesis of NKTCL. REV shows anti-NKTCL activity. The inhibition of PLK1 and the activation of DDR are vital for REV induced tumor cell apoptosis.