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Therapeutic Targeting of Nuclear Gamma-Tubulin in RB1-negative Tumors.

Lindström, Lisa LU ; Villoutreix, Bruno O; Lehn, Sophie LU ; Hellsten, Rebecka LU ; Nilsson, Elise LU ; Crneta, Enisa; Olsson, Roger LU and Alvarado-Kristensson, Maria LU (2015) In Molecular Cancer Research 13(7). p.1073-1082
Abstract
In addition to its cytosolic function, gamma-tubulin is a chromatin-associated protein. Reduced levels of nuclear gamma-tubulin increase the activity of E2 promoter-binding factors (E2F) and raise the levels of retinoblastoma (RB1) tumor suppressor protein. In tumor cells lacking RB1 expression, decreased gamma-tubulin levels induce cell death. Consequently, impairment of the nuclear activity of gamma-tubulin has been suggested as a strategy for targeted chemotherapy of RB1-deficient tumors; thus, tubulin inhibitors were tested to identify compounds that interfere with gamma-tubulin. Interestingly, citral increased E2F activity but impaired microtubule dynamics while citral analogs, like citral dimethyl acetal (CDA), increased E2F activity... (More)
In addition to its cytosolic function, gamma-tubulin is a chromatin-associated protein. Reduced levels of nuclear gamma-tubulin increase the activity of E2 promoter-binding factors (E2F) and raise the levels of retinoblastoma (RB1) tumor suppressor protein. In tumor cells lacking RB1 expression, decreased gamma-tubulin levels induce cell death. Consequently, impairment of the nuclear activity of gamma-tubulin has been suggested as a strategy for targeted chemotherapy of RB1-deficient tumors; thus, tubulin inhibitors were tested to identify compounds that interfere with gamma-tubulin. Interestingly, citral increased E2F activity but impaired microtubule dynamics while citral analogs, like citral dimethyl acetal (CDA), increased E2F activity without affecting microtubules. The cytotoxic effect of CDA on tumor cells was attenuated by increased expression of either RB1 or gamma-tubulin, and increased by reduced levels of either RB1 or gamma-tubulin. Mechanistic study, in silico and in vitro, demonstrated that CDA prevents GTP binding to gamma-tubulin and suggested that the FDA approved drug dimethyl fumarate is also a gamma-tubulin inhibitor. Finally, in vivo growth of xenograft tumors carrying defects in the RB1 signaling pathway were inhibited by CDA treatment. These results demonstrate that inhibition of gamma-tubulin has the potential to specifically target tumor cells and may aid in the design of safer and more efficient chemotherapeutic regimes. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Research
volume
13
issue
7
pages
1073 - 1082
publisher
American Association for Cancer Research
external identifiers
  • pmid:25934692
  • wos:000358059500002
  • scopus:84942321688
ISSN
1557-3125
DOI
10.1158/1541-7786.MCR-15-0063-T
language
English
LU publication?
yes
id
819dbfcd-7c1b-4ca5-87de-b8b0bbf3e569 (old id 5461326)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25934692?dopt=Abstract
date added to LUP
2015-06-04 13:24:45
date last changed
2017-10-22 03:11:08
@article{819dbfcd-7c1b-4ca5-87de-b8b0bbf3e569,
  abstract     = {In addition to its cytosolic function, gamma-tubulin is a chromatin-associated protein. Reduced levels of nuclear gamma-tubulin increase the activity of E2 promoter-binding factors (E2F) and raise the levels of retinoblastoma (RB1) tumor suppressor protein. In tumor cells lacking RB1 expression, decreased gamma-tubulin levels induce cell death. Consequently, impairment of the nuclear activity of gamma-tubulin has been suggested as a strategy for targeted chemotherapy of RB1-deficient tumors; thus, tubulin inhibitors were tested to identify compounds that interfere with gamma-tubulin. Interestingly, citral increased E2F activity but impaired microtubule dynamics while citral analogs, like citral dimethyl acetal (CDA), increased E2F activity without affecting microtubules. The cytotoxic effect of CDA on tumor cells was attenuated by increased expression of either RB1 or gamma-tubulin, and increased by reduced levels of either RB1 or gamma-tubulin. Mechanistic study, in silico and in vitro, demonstrated that CDA prevents GTP binding to gamma-tubulin and suggested that the FDA approved drug dimethyl fumarate is also a gamma-tubulin inhibitor. Finally, in vivo growth of xenograft tumors carrying defects in the RB1 signaling pathway were inhibited by CDA treatment. These results demonstrate that inhibition of gamma-tubulin has the potential to specifically target tumor cells and may aid in the design of safer and more efficient chemotherapeutic regimes.},
  author       = {Lindström, Lisa and Villoutreix, Bruno O and Lehn, Sophie and Hellsten, Rebecka and Nilsson, Elise and Crneta, Enisa and Olsson, Roger and Alvarado-Kristensson, Maria},
  issn         = {1557-3125},
  language     = {eng},
  number       = {7},
  pages        = {1073--1082},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Research},
  title        = {Therapeutic Targeting of Nuclear Gamma-Tubulin in RB1-negative Tumors.},
  url          = {http://dx.doi.org/10.1158/1541-7786.MCR-15-0063-T},
  volume       = {13},
  year         = {2015},
}