title: Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit.
abstract: The anti-tumor effects of chemotherapy and radiation are thought to be mediated by triggering G1/S or G2/M cell cycle checkpoints, while spindle poisons, such as paclitaxel, block metaphase exit by initiating the spindle assembly checkpoint. In contrast, we have found that 150 kilohertz (kHz) alternating electric fields, also known as Tumor Treating Fields (TTFields), perturbed cells at the transition from metaphase to anaphase. Cells exposed to the TTFields during mitosis showed normal progression to this point, but exhibited uncontrolled membrane blebbing that coincided with metaphase exit. The ability of such alternating electric fields to affect cellular physiology is likely to be dependent on their interactions with proteins possessing high dipole moments. The mitotic Septin complex consisting of Septin 2, 6 and 7, possesses a high calculated dipole moment of 2711 Debyes (D) and plays a central role in positioning the cytokinetic cleavage furrow, and governing its contraction during ingression. We showed that during anaphase, TTFields inhibited Septin localization to the anaphase spindle midline and cytokinetic furrow, as well as its association with microtubules during cell attachment and spreading on fibronectin. After aberrant metaphase exit as a consequence of TTFields exposure, cells exhibited aberrant nuclear architecture and signs of cellular stress including an overall decrease in cellular proliferation, followed by apoptosis that was strongly influenced by the p53 mutational status. Thus, TTFields are able to diminish cell proliferation by specifically perturbing key proteins involved in cell division, leading to mitotic catastrophe and subsequent cell death.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Gera
authors.affiliation: Department of Neurology, Division of Neuro-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Yang
authors.affiliation: Department of Neurology, Division of Neuro-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Talia S
authors.initials: TS
authors.lastname: Holtzman
authors.affiliation: Department of Neurology, Division of Neuro-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Sze Xian
authors.initials: SX
authors.lastname: Lee
authors.affiliation: Department of Neurology, Division of Neuro-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Wong
authors.affiliation: Department of Neurology, Division of Neuro-Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Swanson
mesh_terms: D000705:Anaphase; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002877:Chromosomes, Human / Q000378:metabolism; D004560:Electricity; D006801:Humans; D008677:Metaphase; D008938:Mitosis; D008954:Models, Biological; D009369:Neoplasms / Q000473:pathology*; D021381:Protein Transport; D058112:Septins / Q000378:metabolism*; D013312:Stress, Physiological
chemical_list: D058112:Septins