title: A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells.
abstract: Disruption of circadian rhythm is a major cause of breast cancer in humans. Cryptochrome (CRY), a circadian transcription factor, is a risk factor for initiation of breast cancer, and it is differentially expressed between normal and breast cancer tissues. Here, we evaluated the anti-proliferative and pro-apoptotic activity of KS15, a recently discovered small-molecule inhibitor of CRY, in human breast cancer cells. First, we investigated whether KS15 treatment could promote E-box-mediated transcription by inhibiting the activity of CRY in MCF-7 human breast cancer cells. Protein and mRNA levels of regulators of cell cycle and apoptosis, as well as core clock genes, were differentially modulated in response to KS15. Next, we investigated whether KS15 could inhibit proliferation and increase sensitivity to anti-tumor drugs in MCF-7 cells. We found that KS15 decreased the speed of cell growth and increased the chemosensitivity of MCF-7 cells to doxorubicin and tamoxifen, but had no effect on MCF-10A cells. These findings suggested that pharmacological inhibition of CRY by KS15 exerts an anti-proliferative effect and increases sensitivity to anti-tumor drugs in a specific type of breast cancer.
authors.affiliation: Department of Brain & Cognitive Sciences, Daegu-Gyeongbuk Institute of Science & Technology, Daegu, 711-873, South Korea; Department of Biological Sciences, Seoul National University, Seoul, 151-747, South Korea; Department of Brain & Cognitive Sciences, Seoul National University, Seoul, 151-747, South Korea.
authors.forename: Sung Kook
authors.initials: SK
authors.lastname: Chun
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul, 151-747, South Korea; Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 136-705, South Korea.
authors.forename: Sooyoung
authors.initials: S
authors.lastname: Chung
authors.affiliation: Department of Biological Sciences, Seoul National University, Seoul, 151-747, South Korea.
authors.forename: Hee-Dae
authors.initials: HD
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, South Korea.
authors.forename: Ju Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Jaebong
authors.initials: J
authors.lastname: Jang
authors.affiliation: Department of Brain & Cognitive Sciences, Daegu-Gyeongbuk Institute of Science & Technology, Daegu, 711-873, South Korea; Department of Biological Sciences, Seoul National University, Seoul, 151-747, South Korea; Department of Brain & Cognitive Sciences, Seoul National University, Seoul, 151-747, South Korea.
authors.forename: Jeongah
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Brain & Cognitive Sciences, Daegu-Gyeongbuk Institute of Science & Technology, Daegu, 711-873, South Korea; Department of Biological Sciences, Seoul National University, Seoul, 151-747, South Korea; Department of Brain & Cognitive Sciences, Seoul National University, Seoul, 151-747, South Korea.
authors.forename: Doyeon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, 136-705, South Korea.
authors.forename: Gi Hoon
authors.initials: GH
authors.lastname: Son
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, South Korea.
authors.forename: Young J
authors.initials: YJ
authors.lastname: Oh
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.affiliation: Gachon Clinical Trials Center, Gachon University, Incheon, 417-842, South Korea.
authors.forename: Cheol Soon
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Brain & Cognitive Sciences, Daegu-Gyeongbuk Institute of Science & Technology, Daegu, 711-873, South Korea; Department of Biological Sciences, Seoul National University, Seoul, 151-747, South Korea; Department of Brain & Cognitive Sciences, Seoul National University, Seoul, 151-747, South Korea. Electronic address: kyungjin@dgist.ac.kr.
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D009928:Organ Specificity; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D056931:Cryptochromes; D054852:Small Molecule Libraries; D013629:Tamoxifen; D004317:Doxorubicin; D056926:CLOCK Proteins
keywords: Anti-tumor activity; Breast cancer; Cryptochrome; Small molecule