Silencing of tubulin binding cofactor C modifies microtubule dynamics and cell cycle distribution and enhances sensitivity to gemcitabine in breast cancer cells.

Abstract

Tubulin binding cofactor C (TBCC) is essential for the proper folding of α- and β-tubulins into microtubule polymerizable heterodimers. Because microtubules are considered major targets in the treatment of breast cancer, we investigated the influence of TBCC silencing on tubulin pools, microtubule dynamics, and cell cycle distribution of breast cancer cells by developing a variant MCF7 cells with reduced content of TBCC (MC-). MC- cells displayed decreased content in nonpolymerizable tubulins and increased content of polymerizable/microtubule tubulins when compared with control MP6 cells. Microtubules in MC- cells showed stronger dynamics than those of MP6 cells. MC- cells proliferated faster than MP6 cells and showed an altered cell cycle distribution, with a higher percentage in S-phase of the cell cycle. Consequently, MC- cells presented higher sensitivity to the S-phase-targeting agent gemcitabine than MP6 cells in vitro. Although the complete duration of mitosis was shorter in MC- cells and their microtubule dynamics was enhanced, the percentage of cells in G(2)-M phase was not altered nor was there any difference in sensitivity to antimicrotubule-targeting agents when compared with MP6 cells. Xenografts derived from TBCC variants displayed significantly enhanced tumor growth in vivo and increased sensitivity to gemcitabine in comparison to controls. These results are the first to suggest that proteins involved in the proper folding of cytoskeletal components may have an important influence on the cell cycle distribution, proliferation, and chemosensitivity of tumor cells.

• Authors: Rouba Hage-Sleiman, Stéphanie Herveau, Eva-Laure Matera, Jean-Fabien Laurier, Charles Dumontet
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 2 Pg. 303-12 (Feb 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21216936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Molecular Chaperones
• Tubulin
• tubulin-specific chaperone C
• Deoxycytidine
• ARL2 protein, human
• GTP-Binding Proteins
• Gemcitabine

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Breast Neoplasms (physiopathology)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytoplasm (metabolism)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Female
• GTP-Binding Proteins (genetics, metabolism)
• Gene Silencing
• Humans
• Mice
• Mice, SCID
• Microtubules (genetics, metabolism)
• Molecular Chaperones (genetics, metabolism)
• Protein Transport
• Tubulin (genetics, metabolism)
• Xenograft Model Antitumor Assays
• Gemcitabine