Knockdown of TWIST1 enhances arsenic trioxide- and ionizing radiation-induced cell death in lung cancer cells by promoting mitochondrial dysfunction.
TWIST1 is implicated in the process of epithelial mesenchymal transition, metastasis, stemness, and drug resistance in cancer cells, and therefore is a potential target for cancer therapy. In the present study, we found that knockdown of TWIST1 by small interfering RNA (siRNA) enhanced arsenic trioxide (ATO)- and ionizing radiation (IR)-induced cell death in non-small-cell lung cancer cells. Interestingly, intracellular reactive oxygen species levels were increased in cells treated with TWIST1 siRNA and further increased by co-treatment with ATO or IR. Pretreatment of lung cancer cells with the antioxidant N-acetyl-cysteine markedly suppressed the cell death induced by combined treatment with TWIST1 siRNA and ATO or IR. Moreover, treatment of cells with TWIST1 siRNA induced mitochondrial membrane depolarization and significantly increased mitochondrial fragmentation (fission) and upregulated the fission-related proteins FIS1 and DRP1. Collectively, our results demonstrate that siRNA-mediated TWIST1 knockdown induces mitochondrial dysfunction and enhances IR- and ATO-induced cell death in lung cancer cells.
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
Sung-Keum
SK
Seo
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
Jae-Hee
JH
Kim
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
Ha-Na
HN
Choi
Department of Microbiological Engineering, Kon-Kuk University, Gwangjin-gu, Seoul, Republic of Korea.
Tae-Boo
TB
Choe
Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
Seok-Il
SI
Hong
Laboratory of Modulation of Radiobiological Responses, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
Jae-Youn
JY
Yi
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea.
Sang-Gu
SG
Hwang
Department of Microbiology and Immunology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul, Republic of Korea.
Hyun-Gyu
HG
Lee
Department of Radiation Oncology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul, Republic of Korea. Electronic address: yhlee87@yuhs.ac.
Yun-Han
YH
Lee
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul, Republic of Korea. Electronic address: parkic@kcch.re.kr.
In-Chul
IC
Park
D000111:Acetylcysteine / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D055785:Gene Knockdown Techniques; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D010087:Oxides; D034741:RNA, Small Interfering / Q000494:pharmacology; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000096:biosynthesis / Q000235:genetics*
D001152:Arsenicals; D009687:Nuclear Proteins; D010087:Oxides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D000077237:Arsenic Trioxide; D000111:Acetylcysteine
Arsenic trioxide; Irradiation; Mitochondria dysfunction; Reactive oxygen species; TWIST1