title: Bmal1 suppresses cancer cell invasion by blocking the phosphoinositide 3-kinase-Akt-MMP-2 signaling pathway.
abstract: Bmal1 is a core factor in the regulation of circadian rhythms. Previous studies have shown that Bmal1 suppresses tumor growth in cell culture and animal models and is downregulated in certain types of cancer. The aim of the present study was to investigated whether Bmal1 influences the invasiveness of cancer cells. We demonstrated that knockdown of Bmal1 by RNA interference promoted cancer cell invasion, whereas its overexpression reduced cellular invasiveness. These effects were observed in lung cancer and glioma cells, and occurred regardless of p53 status. Therefore, it appears that Bmal1 suppresses the invasion of multiple cancer types in a p53-independent manner. Bmal1 knockdown-induced cancer cell invasion was accompanied by activation of the PI3K-Akt-MMP-2 pathway, and was prevented by inhibitors of PI3K, Akt or MMP-2. This suggests that Bmal1 suppresses cell invasion by blocking the PI3K-Akt-MMP-2 pathway. Since this invasion pathway is activated by the oncogene Bcl-w, we investigated whether Bmal1 affects the activity of Bcl-w. As expected, Bmal1 attenuated the ability of Bcl-w to promote MMP-2 accumulation and cell invasion, supporting the idea that Bmal1 antagonizes Bcl-w activity. Collectively, our data suggest that Bmal1 is a tumor suppressor, capable of suppressing cancer cell growth and invasiveness, and support the recent proposal that there is a tight molecular link between circadian rhythms and tumor formation/progression.
authors.affiliation: Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Chan-Hun
authors.initials: CH
authors.lastname: Jung
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Kim
authors.forename: Jong Kuk
authors.initials: JK
authors.lastname: Park
authors.forename: Sang-Gu
authors.initials: SG
authors.lastname: Hwang
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
mesh_terms: D056930:ARNTL Transcription Factors / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; D051017:Apoptosis Regulatory Proteins; C491073:BCL2L2 protein, human; D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
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