Spindle Assembly Disruption and Cancer Cell Apoptosis with a CLTC-Binding Compound
| Autor: | Narendran G-Dayanan, Santosh Keshipeddy, Marina Bleiler, Eric W. Scocchera, Masako Nakanishi, Charles Giardina, Michael J Bond, Daniel W. Rosenberg, Lauren E Harrison, Dennis L. Wright |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cancer Research Mitosis Apoptosis Spindle Apparatus Transfection Clathrin Article Piperazines Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Animals Humans Molecular Targeted Therapy Molecular Biology Cellular localization biology Chemistry HCT116 Cells Spindle apparatus 030104 developmental biology Oncology Centrosome Clathrin Heavy Chains Gene Knockdown Techniques 030220 oncology & carcinogenesis Colonic Neoplasms Cancer cell Cancer research biology.protein CLTC Multipolar spindles |
| Zdroj: | Molecular Cancer Research. 16:1361-1372 |
| ISSN: | 1557-3125 1541-7786 |
| DOI: | 10.1158/1541-7786.mcr-18-0178 |
| Popis: | AK3 compounds are mitotic arrest agents that induce high levels of γH2AX during mitosis and apoptosis following release from arrest. We synthesized a potent AK3 derivative, AK306, that induced arrest and apoptosis of the HCT116 colon cancer cell line with an EC50 of approximately 50 nmol/L. AK306 was active on a broad spectrum of cancer cell lines with total growth inhibition values ranging from approximately 25 nmol/L to 25 μmol/L. Using biotin and BODIPY-linked derivatives of AK306, binding to clathrin heavy chain (CLTC/CHC) was observed, a protein with roles in endocytosis and mitosis. AK306 inhibited mitosis and endocytosis, while disrupting CHC cellular localization. Cells arrested in mitosis by AK306 showed the formation of multiple microtubule-organizing centers consisting of pericentrin, γ-tubulin, and Aurora A foci, without apparent centrosome amplification. Cells released from AK306 arrest were unable to form bipolar spindles, unlike nocodazole-released cells that reformed spindles and completed division. Like AK306, CHC siRNA knockdown disrupted spindle formation and activated p53. A short-term (3-day) treatment of tumor-bearing APC-mutant mice with AK306 increased apoptosis in tumors, but not normal mucosa. These findings indicate that targeting the mitotic CHC complex can selectively induce apoptosis and may have therapeutic value. Implication: Disruption of clathrin with a small-molecule inhibitor, AK306, selectively induces apoptosis in cancer cells by disrupting bipolar spindle formation. Mol Cancer Res; 16(9); 1361–72. ©2018 AACR. |
| Databáze: | OpenAIRE |
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