High-Speed Atomic Force Microscopy Reveals Loss of Nuclear Pore Resilience as a Dying Code in Colorectal Cancer Cells

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 ∼30 proteins, termed nucleoporins. About one-third of nucleoporins harbor natively unstructured, intrinsica...

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Published in:ACS nano 2017-06, Vol.11 (6), p.5567-5578
Main Authors: Mohamed, Mahmoud Shaaban, Kobayashi, Akiko, Taoka, Azuma, Watanabe-Nakayama, Takahiro, Kikuchi, Yosuke, Hazawa, Masaharu, Minamoto, Toshinari, Fukumori, Yoshihiro, Kodera, Noriyuki, Uchihashi, Takayuki, Ando, Toshio, Wong, Richard W
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Azepines - pharmacology
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
HCT116 Cells
Humans
Microscopy, Atomic Force - methods
Nuclear Pore - drug effects
Nuclear Pore - metabolism
Nuclear Pore - pathology
Nuclear Pore Complex Proteins - analysis
Nuclear Pore Complex Proteins - metabolism
Protein Kinase Inhibitors - pharmacology
Pyrimidines - pharmacology
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Summary: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 ∼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.
ISSN:1936-0851
1936-086X
DOI:10.1021/acsnano.7b00906