Therapeutic Targeting of Nuclear Gamma-Tubulin in RB1-negative Tumors.
(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:
https://lup.lub.lu.se/record/5461326
- author
- 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
- organization
- publishing date
- 2015
- 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
- pmid:25934692
- ISSN
- 1557-3125
- DOI
- 10.1158/1541-7786.MCR-15-0063-T
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Pathology (Malmö) (013031000), Division of Urological Cancers (013243420), Pathology, (Lund) (013030000), Molecular pathology (013031700), Chemical Biology and Drug Discovery (013210700)
- id
- 819dbfcd-7c1b-4ca5-87de-b8b0bbf3e569 (old id 5461326)
- date added to LUP
- 2016-04-01 10:15:45
- date last changed
- 2022-04-12 03:40:58
@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}}, doi = {{10.1158/1541-7786.MCR-15-0063-T}}, volume = {{13}}, year = {{2015}}, }