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

// Poyil Pratheeshkumar 1, 2, * , Young-Ok Son 1, 2, * , Sasidharan Padmaja Divya 1, 2 , Lei Wang 1, 2 , Lilia Turcios 3 , Ram Vinod Roy 1, 2 , John Andrew Hitron 1, 2 , Donghern Kim 2 , Jin Dai 2 , Padmaja Asha 4 , Zhuo Zhang 2 , Xianglin Shi 1, 2 1 Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA 2 Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA 3 Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY, USA 4 National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin, India * These authors have contributed equally to this work Correspondence to: Xianglin Shi, email: xshi5@email.uky.edu Keywords: hexavalent chromium, quercetin, ROS, malignant cell transformation, miR-21-PDCD4 signaling Received: April 16, 2016      Accepted: June 03, 2016      Published: June 17, 2016 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.