期刊
ACS NANO
卷 11, 期 6, 页码 5567-5578出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.7b00906
关键词
high-speed atomic force microscopy; live cell imaging; nanopore; nuclear pore complex; colon cancer
类别
资金
- MEXT/JSPS [24227005, 24117007, 15H04928]
- MEXT Japan [17H05874, 17K08655]
- Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University
- Uehara Memorial Foundation
- Suzuken Memorial Foundation
- Asahi Glass Foundation
- Kowa Life Science Foundation
- Sumitomo Foundation
- Mochida Memorial Foundation
- Sagawa Foundation
- Ichiro Kanehara Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [17H05874, 15H04360, 15H04928, 17K16332, 26119003, 17H06121, 24117007, 17K19345, 17K08655] Funding Source: KAKEN
Nuclear pore complexes (NPCs) are the sole turnstile implanted in the nuclear envelope (NE), acting as a central nanoregulator of transport between the cytosol and the nucleus. NPCs consist of similar to 30 proteins, termed nucleoporins. About one-third of nucleoporins harbor natively unstructured, intrinsically disordered phenylalanine-glycine strings (FG-Nups), which engage in transport selectivity. Because the barriers insert deeply in the NPC, they are nearly inaccessible. Several in vitro barrier models have been proposed; however, the dynamic FG-Nups protein molecules themselves are imperceptible in vivo. We show here that high-speed atomic force microscopy (HS-AFM) can be used to directly visualize nanotopographical changes of the nuclear pore inner channel in colorectal cancer (CRC) cells. Furthermore, using MLN8237/alisertib, an apoptotic and autophagic inducer currently being tested in relapsed cancer clinical trials, we unveiled the functional loss of nucleoporins, particularly the deformation of the FG-Nups barrier, in dying cancer cells. We propose that the loss of this nanoscopic resilience is an irreversible dying code in cells. These findings not only illuminate the potential application of HS-AFM as an intracellular nanoendoscopy but also might aid in the design of future nuclear targeted nanodrug delivery tailored to the individual patient.
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