Quercetin inhibits Cr(VI)-induced malignant cell transformation by targeting miR-21-PDCD4 signaling pathway
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Poyil Pratheeshkumar1,2,*, Young-Ok Son1,2,*, Sasidharan Padmaja Divya1,2, Lei Wang1,2, Lilia Turcios3, Ram Vinod Roy1,2, John Andrew Hitron1,2, Donghern Kim2, Jin Dai2, Padmaja Asha4, Zhuo Zhang2, Xianglin Shi1,2
1Center for Research on Environmental Disease, University of Kentucky, Lexington, KY, USA
2Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA
3Department of Surgery, University of Kentucky, College of Medicine, Lexington, KY, USA
4National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin, India
*These authors have contributed equally to this work
Xianglin Shi, email: [email protected]
Keywords: hexavalent chromium, quercetin, ROS, malignant cell transformation, miR-21-PDCD4 signaling
Received: April 16, 2016 Accepted: June 03, 2016 Published: June 17, 2016
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.
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