Drug resistance to 5-FU linked to reactive oxygen species modulator 1.
While acute oxidative stress triggers cell apoptosis or necrosis, persistent oxidative stress induces genomic instability and has been implicated in tumor progression and drug resistance. In a previous report, we demonstrated that reactive oxygen species modulator 1 (Romo1) expression was up-regulated in most cancer cell lines and suggested that increased Romo1 expression might confer chronic oxidative stress to tumor cells. In this study, we show that enforced Romo1 expression induces reactive oxygen species (ROS) production in the mitochondria leading to massive cell death. However, tumor cells that adapt to oxidative stress by increasing manganese superoxide dismutase (MnSOD), Prx I, and Bcl-2 showed drug resistance to 5-FU. To elucidate the relationship between 5-FU-induced ROS production and Romo1 expression, Romo1 siRNA was used to inhibit 5-FU-triggered Romo1 induction. Romo1 siRNA treatment efficiently blocked 5-FU-induced ROS generation, demonstrating that 5-FU treatment stimulated ROS production through Romo1 induction. Based on these results we suggest that cellular adaptive response to Romo1-induced ROS is another mechanism of drug resistance to 5-FU and Romo1 expression may provide a new clinical implication in drug resistance of cancer chemotherapy.
Hwang
In Tae
IT
Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul, Republic of Korea.
Chung
Young Min
YM
Kim
Jung Jin
JJ
Chung
Jin Sil
JS
Kim
Byung Soo
BS
Kim
Hyung Jung
HJ
Kim
Jun Suk
JS
Yoo
Young Do
YD
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial; D008565:Membrane Proteins / Q000096:biosynthesis*; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species; D013050:Spectrometry, Fluorescence; D013997:Time Factors
D000964:Antimetabolites, Antineoplastic; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C513338:ROMO1 protein, human; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D005472:Fluorouracil