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

Xianxian Sui; Canjing Zhang; Yudong Jiang; Jianan Zhou; Chen Xu; Feng Tang; Bobin Chen; Huiwen Xu; Songmei Wang; Xuanyi Wang

doi:10.21037/atm-19-4324

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

Ann Transl Med. 2020 Jun;8(11):688. doi: 10.21037/atm-19-4324.

Authors

Xianxian Sui¹, Canjing Zhang², Yudong Jiang³, Jianan Zhou⁴, Chen Xu⁵, Feng Tang⁶, Bobin Chen⁷, Huiwen Xu⁷, Songmei Wang¹, Xuanyi Wang²

Affiliations

¹ Laboratory of Medical Molecular Biology, Experimental Teaching Center, School of Basic Medical Sciences, Fudan University, Shanghai, China.
² Key Laboratory of Medical Molecular Virology of Ministry of Education & Ministry of Health, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
³ Shanghai Medical College, Fudan University, Shanghai, China.
⁴ The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
⁵ Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
⁷ Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.

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.

Keywords: DNA damage response pathway (DDR pathway); Extranodal natural killer/T cell lymphoma (NKTCL); checkpoint kinase 2 (Chk2); polo-like kinase 1 (PLK1); resveratrol (REV).