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: Sung Kook Chun, Sooyoung Chung, Hee-Dae Kim, Ju Hyung Lee, Jaebong Jang, Jeongah Kim, Doyeon Kim, Gi Hoon Son, Young J Oh, Young-Ger Suh, Cheol Soon Lee, Kyungjin Kim
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 467 Issue 2 Pg. 441-6 (Nov 13 2015) ISSN: 1090-2104 [Electronic] United States
• PMID: 26407844 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cryptochromes
• Small Molecule Libraries
• Tamoxifen
• Doxorubicin
• CLOCK Proteins

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• CLOCK Proteins (genetics, metabolism)
• Cell Cycle (drug effects)
• Cell Survival (drug effects)
• Circadian Rhythm (genetics)
• Cryptochromes (antagonists & inhibitors, genetics, metabolism)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Organ Specificity
• Signal Transduction
• Small Molecule Libraries (pharmacology)
• Tamoxifen (pharmacology)