Quercetin inhibits Cr(VI)-induced malignant cell transformation by targeting miR-21-PDCD4 signaling pathway.

Poyil Pratheeshkumar,Sasidharan Padmaja Divya,Lilia Turcios,Lei Wang,Young-Ok Son,Jin Dai,Xianglin Shi,Zhuo Zhang,Ram Vinod Roy,Padmaja Asha,Donghern Kim,John Andrew Hitron

doi:10.18632/oncotarget.10130

Poyil Pratheeshkumar, Sasidharan Padmaja Divya + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.10130

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Abstract

Hexavalent chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Inhibition of Cr(VI)-induced carcinogenesis by a dietary antioxidant is a novel approach. Quercetin is one of the most abundant dietary flavonoids widely present in many fruits and vegetables, possesses potent antioxidant and anticancer properties. MicroRNA-21 (miR-21) is a key oncomiR significantly elevated in the majority of human cancers that exerts its oncogenic activity by targeting the tumor suppressor gene programmed cell death 4 (PDCD4). The present study examined the effect of quercetin on the inhibition of Cr(VI)-induced malignant cell transformation and the role of miR-21-PDCD4 signaling involved. Our results showed that quercetin decreased ROS generation induced by Cr(VI) exposure in BEAS-2B cells. Chronic Cr(VI) exposure induced malignant cell transformation, increased miR-21 expression and caused inhibition of PDCD4, which were significantly inhibited by the treatment of quercetin in a dose dependent manner. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of quercetin showed reduced tumor incidence compared to Cr(VI) alone treated group. Stable knockdown of miR-21 and overexpression of PDCD4 or catalase in BEAS-2B cells suppressed Cr(VI)-induced malignant transformation and tumorigenesis. Taken together, these results demonstrate that quercetin is able to protect BEAS-2B cells from Cr(VI)-induced carcinogenesis by targeting miR-21-PDCD4 signaling.

Highlights

Lung cancer is globally responsible for 1.4 million deaths annually and is the leading cause of cancerrelated deaths in both women and men [1]
The present study examined the effect of quercetin on the inhibition of Cr(VI)-induced malignant cell transformation and the role of miR-21-programmed cell death 4 (PDCD4) signaling involved
Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of quercetin showed reduced tumor incidence compared to Cr(VI) alone treated group

Summary

INTRODUCTION

Lung cancer is globally responsible for 1.4 million deaths annually and is the leading cause of cancerrelated deaths in both women and men [1]. Among www.impactjournals.com/oncotarget various miRNAs, miR-21 described as a key oncomiR [6], was found to be overexpressed in different types of human cancers and implicated in various aspects of carcinogenesis, apoptosis resistance, cell proliferation, tumor progression, invasion and chemoresistance [7,8,9,10,11,12,13,14]. We found that quercetin inhibited Cr(VI)-induced miR21 elevation and PDCD4 reduction thereby inhibited malignant transformation of BEAS-2B cells. The treatment of quercetin significantly inhibited the Cr(VI)induced ROS generation, where ROS is critical for miR21 elevation and PDCD4 reduction in Cr(VI)-induced malignant transformation. Quercetin suppressed the Cr(VI)-induced tumorigenicity of BEAS2B cells in Nude mice These results suggest that quercetin protects BEAS-2B cells from Cr(VI)-induced malignant transformation by targeting miR-21 and PDCD4 signaling pathways

RESULTS

DISCUSSION

MATERIALS AND METHODS