Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways

Title
Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways
Author(s)
정태천Minh Truong Do[Minh Truong Do]김형균[김형균]Tilak Khanal[Tilak Khanal]최재호[최재호]김동희[김동희]정혜광[정혜광]
Keywords
ANTIOXIDANT RESPONSE ELEMENT; CHRONIC LIVER-DISEASE; TUMOR-GROWTH; DIABETIC-PATIENTS; LUNG-CANCER; HEPATOCELLULAR-CARCINOMA; TRANSCRIPTIONAL ACTIVITY; ANTICANCER TREATMENT; PANCREATIC-CANCER; GENE-EXPRESSION
Issue Date
201309
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Citation
TOXICOLOGY AND APPLIED PHARMACOLOGY, v.271, no.2, pp.229 - 238
Abstract
Resistance to therapy is the major obstacle to more effective cancer treatment. Heme oxygenase-1 (HO-1) is often highly up-regulated in tumor tissues, and its expression is further increased in response to therapies. It has been suggested that inhibition of HO-1 expression is a potential therapeutic approach to sensitize tumors to chemotherapy and radiotherapy. In this study, we tested the hypothesis that the anti-tumor effects of metformin are mediated by suppression of HO-1 expression in cancer cells. Our results indicate that metformin strongly suppresses HO-1 mRNA and protein expression in human hepatic carcinoma HepG2, cervical cancer HeLa, and non-small-cell lung cancer A549 cells. Metformin also markedly reduced Nrf2 mRNA and protein levels in whole cell lysates and suppressed tert-butylhydroquinone (tBHQ)-induced Nrf2 protein stability and antioxidant response element (ARE)-luciferase activity in HepG2 cells. We also found that metformin regulation of Nrf2 expression is mediated by a Keap1-independent mechanism and that metformin significantly attenuated Raf-ERK signaling to suppress Nrf2 expression in cancer cells. Inhibition of Raf-ERK signaling by PD98059 decreased Nrf2 mRNA expression in HepG2 cells, confirming that the inhibition of Nrf2 expression is mediated by an attenuation of Raf-ERK signaling in cancer cells. The inactivation of AMPK by siRNA, DN-AMPK or the pharmacological AMPK inhibitor compound C, revealed that metformin reduced HO-1 expression in an AMPK-independent manner. These results highlight the Raf-ERK-Nrf2 axis as a new molecular target in anticancer therapy in response to metformin treatment. (C) 2013 Elsevier Inc. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/28986http://dx.doi.org/10.1016/j.taap.2013.05.010
ISSN
0041-008X
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약학대학 > 약학부 > Articles
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