Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells.
Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA-MB-231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting the growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1-mediated ETC-dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC-deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria-targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism.
Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
Kazunori
K
Mori
Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
Tetsu
T
Uchida
Department of Medicinal Chemistry, Showa University School of Pharmacy, Tokyo, Japan.
Motonori
M
Fukumura
Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
Shigetoshi
S
Tamiya
Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
Masato
M
Higurashi
Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
Hirosato
H
Sakai
Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
Fumihiro
F
Ishikawa
Department of Molecular Biology, Showa University School of Pharmacy, Tokyo, Japan.
Motoko
M
Shibanuma
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003260:Contact Inhibition; D004268:DNA-Binding Proteins / Q000172:deficiency; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D004579:Electron Transport / Q000235:genetics; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D024101:Mitochondrial Proteins / Q000172:deficiency; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C064352:MYBL2 protein, human; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D014157:Transcription Factors; C422562:mitochondrial transcription factor A
Breast neoplasm; E2F1 transcription factor; cell cycle; electron transport; reactive oxygen species