Therapeutic Targeting of Nuclear γ-Tubulin in RB1-Negative Tumors.
In addition to its cytosolic function, γ-tubulin is a chromatin-associated protein. Reduced levels of nuclear γ-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 γ-tubulin levels induce cell death. Consequently, impairment of the nuclear activity of γ-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 γ-tubulin. Interestingly, citral increased E2F activity but impaired microtubule dynamics while citral analogues, such 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 γ-tubulin, and increased by reduced levels of either RB1 or γ-tubulin. Mechanistic study, in silico and in vitro, demonstrated that CDA prevents GTP binding to γ-tubulin and suggested that the FDA-approved drug dimethyl fumarate is also a γ-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 γ-tubulin has the potential to specifically target tumor cells and may aid in the design of safer and more efficient chemotherapeutic regimes.


CONCLUSIONS
The in vivo antitumorigenic activity of γ-tubulin inhibitors paves the way for the development of a novel broad range targeted anticancer therapy that causes fewer side effects.
Molecular Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
Lisa
L
Lindström
Université Paris Diderot, Sorbonne Paris Cité, UMRS 973 Inserm, Paris, France. Inserm, U973, Paris, France.
Bruno O
BO
Villoutreix
Molecular Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
Sophie
S
Lehn
Division of Urological Cancers, Lund University, Skåne University Hospital, Malmö, Sweden.
Rebecka
R
Hellsten
Molecular Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
Elise
E
Nilsson
Molecular Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
Enisa
E
Crneta
Chemical Biology and Therapeutics, Department of Experimental Medical Science, BMC, Lund University, Lund, Sweden.
Roger
R
Olsson
Molecular Pathology, Department of Translational Medicine, Lund University, Skåne University Hospital, Malmö, Sweden. maria.alvarado-kristensson@med.lu.se.
Maria
M
Alvarado-Kristensson
D000080:Acetals / Q000494:pharmacology*; D000080462:Acyclic Monoterpenes; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000378:metabolism; D000069462:Dimethyl Fumarate / Q000494:pharmacology; D050684:E2F Transcription Factors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D064593:Heterografts; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
D000080:Acetals; D000080462:Acyclic Monoterpenes; D000970:Antineoplastic Agents; D050684:E2F Transcription Factors; D039821:Monoterpenes; D009687:Nuclear Proteins; D016160:Retinoblastoma Protein; D014404:Tubulin; D050257:Tubulin Modulators; C000606134:citral dimethyl acetal; D006160:Guanosine Triphosphate; D000069462:Dimethyl Fumarate; D003545:Cysteine; C007076:citral