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Therapeutic Targeti...
Therapeutic Targeting of Nuclear Gamma-Tubulin in RB1-negative Tumors.
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- Lindström, Lisa (författare)
- Lund University,Lunds universitet,Molekylär patologi, Malmö,Forskargrupper vid Lunds universitet,Molecular Pathology, Malmö,Lund University Research Groups
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Villoutreix, Bruno O (författare)
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- Lehn, Sophie (författare)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Molekylär patologi, Malmö,Forskargrupper vid Lunds universitet,Patologi, Malmö,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Molecular Pathology, Malmö,Lund University Research Groups,Pathology, Malmö
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- Hellsten, Rebecka (författare)
- Lund University,Lunds universitet,Urologisk cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Urological cancer, Malmö,Lund University Research Groups
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- Nilsson, Elise (författare)
- Lund University,Lunds universitet,Urologisk cancerforskning, Malmö,Forskargrupper vid Lunds universitet,Patologi, Malmö,Urological cancer, Malmö,Lund University Research Groups,Pathology, Malmö
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Crneta, Enisa (författare)
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- Olsson, Roger (författare)
- Lund University,Lunds universitet,Kemisk biologi med inriktning mot läkemedelsutveckling,Forskargrupper vid Lunds universitet,Chemical Biology and Therapeutics,Lund University Research Groups
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- Alvarado-Kristensson, Maria (författare)
- Lund University,Lunds universitet,Molekylär patologi, Malmö,Forskargrupper vid Lunds universitet,Patologi, Malmö,Molecular Pathology, Malmö,Lund University Research Groups,Pathology, Malmö
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(creator_code:org_t)
- 2015
- 2015
- Engelska.
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Ingår i: Molecular Cancer Research. - 1557-3125. ; 13:7, s. 1073-1082
- Relaterad länk:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- art (ämneskategori)
- ref (ämneskategori)
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