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 a-and b-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 (MCÀ). MCÀ cells displayed decreased content in nonpolymerizable tubulins and increased content of polymerizable/microtubule tubulins when compared with control MP6 cells. Microtubules in MCÀ cells showed stronger dynamics than those of MP6 cells. MCÀ 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, MCÀ 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 MCÀ 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. Mol Cancer Ther; 10(2); 303-12. Ó2011 AACR.

Proteomic analysis of gemcitabine-resistant pancreatic cancer cells reveals that microtubule-associated protein 2 upregulation associates with taxane treatment

“…A previous study showed that modulation of microtubule dynamics by the silencing of tubulin binding cofactor C and cell cycle distribution enhanced the sensitivity to gemcitabine in breast cancer cells. 39 Furthermore, the combination of the benzophenone analogue S516, which changed the cellular microtubule network, with gemcitabine significantly delayed the growth of lung cancer tumours as compared with control and gemcitabine alone. 40…”

S100A4 Is a Biomarker of Tumorigenesis, EMT, Invasion, and Colonization of Host Organs in Experimental Malignant Mesothelioma

“…TBCA is a member of a family of proteins that act at different levels of a folding pathway to generate tubulin heterodimers involved in many cellular functions. As two independent studies have reported a role for these chaperones in the sensitivity/resistance to treatment of different types of cancer [57,58], the similarity of S100A4 and TBCA profiles in rat spleen in the context of MM progression is intriguing. The additional data on ANXA2 finally suggest that markers of communication between cells/intracellular transport, cell motility, and cellular architecture are closely interconnected, especially in the more advanced stages, highlighting the key role of the S100A4/annexin A2 interaction [59].…”

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins

“…Given the importance of MTs in cell division and the widely accepted concept that cancer cells divide more rapidly than normal cells, it has been generally assumed that MTAs mediate cytotoxicity by interfering with mitosis (1, 2). Elegant in vitro and preclinical data have demonstrated time and again that MTAs lead to mitotic arrest and in turn cell death (5,(7)(8)(9)(10)(11)(12). Arrest in mitosis as the mechanism that leads to cell death is possible in these preclinical models because their doubling times range from a few hours to at most a few days, and even brief drug exposures are likely to encounter a substantial fraction of cells traversing through mitosis.…”