Tumors with Nonfunctional Retinoblastoma Protein Are Killed by Reduced γ-Tubulin Levels

Ehlén, Åsa; Rosselló, Catalina Ana; Stedingk, Kristoffer von; Höög, Greta; Nilsson, Elise; Pettersson, Helen; Jirström, Karin; Alvarado-Kristensson, María

doi:10.1074/jbc.m112.357038

Cited by 26 publications

(51 citation statements)

References 24 publications

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“…In various tumors and cell lines, the localization and expression of g-tubulin are altered (10)(11)(12). In line with these findings, we discovered a mechanism allowing g-tubulin and retinoblastoma protein (RB1) to moderate each other's expression by direct binding to E2F-binding sites on TUBG and RB1 promoter regions (6). In the absence of g-tubulin and RB1, E2F activity leads to cellular death, whereas in the presence of RB1, absence of g-tubulin activity causes an increase in RB1 protein levels (6,7).…”

Section: Introductionmentioning

confidence: 83%

“…We have previously described that during S-phase, g-tubulin moderates the activity of E2F1 and absence of g-tubulin activity is compensated by RB1. Simultaneous reduction of RB1 and g-tubulin activities inactivates the G 1 to S transition checkpoint and an uncontrolled E2F1 activity leads to a subsequent G 2 -M checkpoint activation and cell death (6). Thus, the development of drugs that specifically inhibit g-tubulin activity has the potential to pave the way for chemotherapies that target only tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…To investigate whether this unexpected effect was real, we studied the protein expression of RB1 protein and pRB1 phosphorylated on Ser 780 (6,29) in tumors from mice implanted with U1690RB1. An almost undetectable amount of RB1 protein, which was also highly phosphorylated, was detected in both CDA and vehicle-treated tumors (Fig.…”

Section: Cda Treatment Delays Xenograft Tumor Growth In Tumor Cells Wmentioning

confidence: 99%

“…We and others have shown that in addition to its cytosolic function, g-tubulin is a chromatinassociated protein that binds to Rad51, C53, and E2 promoter-binding factor 1 (E2F1; refs. [6][7][8][9]. In various tumors and cell lines, the localization and expression of g-tubulin are altered (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

“…In the absence of g-tubulin and RB1, E2F activity leads to cellular death, whereas in the presence of RB1, absence of g-tubulin activity causes an increase in RB1 protein levels (6,7). As the RB-signaling pathway is one of the most distorted signal pathways in cancer cells (6,13), the development of drugs that specifically inhibit g-tubulin activity has the potential to pave the way for chemotherapies that target tumor cells from multiple malignancies but have no impact on healthy cells.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic Targeting of Nuclear γ-Tubulin in RB1-Negative Tumors

Lindström

Villoutreix

Lehn

et al. 2015

Molecular Cancer Research

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In addition to its cytosolic function, g-tubulin is a chromatinassociated protein. Reduced levels of nuclear g-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 g-tubulin levels induce cell death. Consequently, impairment of the nuclear activity of g-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 g-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 g-tubulin, and increased by reduced levels of either RB1 or g-tubulin. Mechanistic study, in silico and in vitro, demonstrated that CDA prevents GTP binding to g-tubulin and suggested that the FDA-approved drug dimethyl fumarate is also a g-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 g-tubulin has the potential to specifically target tumor cells and may aid in the design of safer and more efficient chemotherapeutic regimes. Implications:The in vivo antitumorigenic activity of g-tubulin inhibitors paves the way for the development of a novel broad range targeted anticancer therapy that causes fewer side effects.

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Section: Introductionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Cda Treatment Delays Xenograft Tumor Growth In Tumor Cells Wmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Therapeutic Targeting of Nuclear γ-Tubulin in RB1-Negative Tumors

Lindström

Villoutreix

Lehn

et al. 2015

Molecular Cancer Research

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The common diabetes drug metformin can diminish the action of citral against Rhabdomyosarcoma cells in vitro

Duan

Evison

Taylor

et al. 2020

Phytotherapy Research

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Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma most commonly found in pediatric patients. Despite progress, new and improved drug regimens are needed to increase survival rates. Citral, a natural product plant oil can induce cell death in cancer cells. Another compound, metformin, isolated originally from French lilac and used by diabetics, has been shown to reduce the incidence of cancer in these patients. Application of citral to RMS cells showed increase in cell death, and RD and RH30 cells showed half maximal inhibitory concentration (IC50) values as low as 36.28 μM and 62.37 μM, respectively. It was also shown that the citral initiated cell apoptosis through an increase in reactive oxygen species (ROS) and free calcium. In comparison, metformin only showed moderate cell death in RMS cell lines at a very high concentration (1,000 μM). Combinatorial experiments, however, indicated that citral and metformin worked antagonistically when used together. In particular, the ability of metformin to quench the ROS induced by citral could lead to the suppression of activity. These results clearly indicate that while clinical use of citral is a promising anti‐tumor therapy, caution should be exercised in patients using metformin for diabetes.

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A Hypothesis on the Origin and Evolution of Tubulin

Ludueña

2013

International Review of Cell and Molecular Biology

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Tumors with Nonfunctional Retinoblastoma Protein Are Killed by Reduced γ-Tubulin Levels

Cited by 26 publications

References 24 publications

Therapeutic Targeting of Nuclear γ-Tubulin in RB1-Negative Tumors

Therapeutic Targeting of Nuclear γ-Tubulin in RB1-Negative Tumors

The common diabetes drug metformin can diminish the action of citral against Rhabdomyosarcoma cells in vitro

A Hypothesis on the Origin and Evolution of Tubulin

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