Inhibition of Human Breast Cancer Cell Growth by Blockade of the Mevalonate-Protein Prenylation Pathway is not Prevented by Overexpression of Cyclin D1

Springer Science and Business Media LLC - Tập 67 - Trang 23-33 - 2001
Domenico Germano1, Carmen Pacilio1, Massimo Cancemi1, Luigi Cicatiello1, Lucia Altucci1, Valeria Belsito Petrizzi1, Carmine Sperandio1, Salvatore Salzano2, Rob J.A.M. Michalides3, Yoichi Taya4, Francesco Bresciani1, Alessandro Weisz1
1Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli, Naples, Italy
2Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche/Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘L. Califano’, Università ‘Federico II’, Naples, Italy
3Department of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
4Biology Division, National Cancer Center Research Institute, Tokyo, Japan

Tóm tắt

Overexpression of the cyclin D1 (CCND1) gene, encoding a downstream effector of mitogenic signals that plays a central role in G1 phase progression, is often found in cancerous cells. In sporadic breast cancer (BC), this is one of the most frequent and early genetic lesions identified so far, found in more than 50% of the tumors. Inhibitors of the mevalonate/protein prenylation pathway belong to a new family of cancer therapeutic agents that act by blocking intracellular mitogenic signal transduction pathways, thereby preventing expansion of pre-cancerous foci and inhibiting growth of transformed cells. It is not known at present whether constitutively high intracellular levels of cyclin D1 might interfere with the cytostatic actions of mevalonate/protein prenylation inhibitors. This possibility was investigated here by assessing the cell cycle effects of Simvastatin, a non-toxic upstream inhibitor of the mevalonate pathway, on human BC MCF-7 cells expressing either normal or enhanced levels of cyclin D1 from of a stably transfected, tet-inducible expression vector. Results show that constitutive overexpression of this protein, such as that found in sporadic BCs, does not influence the growth inhibitory effects of Simvastatin in vitro. In addition, D1-overexpressing embryo fibroblasts were also found to be responsive to the cell cycle effects of mevalonate/protein prenylation pathway blockade, further suggesting that high intracellular levels of cyclin D1 do not prevent the cytostatic actions of compounds targeting this metabolic pathway.

Tài liệu tham khảo

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