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

Abstract

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.